eisenmenger syndrome in detail

1. Eisenmenger syndrome

2. Index
1. Brief overview of history
2. Definition
3. Epidemiology
4. Pathophysiology
5. Causes
6. Classification
7. Clinical Presentation
8. Differential Diagnosis
9. Complications
10.Investigations
11.Management
12.Natural History

3. First Description
• “The patient was a powerfully built man of 32 who gave
a history of cyanosis and moderate breathlessness since
infancy.
• He managed well enough ,until January 1894 when
dyspnoea increased and edema set in. Seven months
later he was admitted to hospital in a state of heart
failure.
• He improved with rest and digitalis, but collapsed and
died more or less suddenly on November 13 following a
large hemoptysis.
• At necropsy , a 2 –to 2.5 cm defect was found in the
perimembranous septum” – Dr Victor Eisenmenger,1897

4. • 1897  Austrian pathologist Victor Eisenmenger
described postmortem findings of VSD  adult
patient who died of cyanosis and DOE
• “Eisenmenger complex” term was coined by
MAUDE ABOTT in 1927
– VSD with reversed shunt in absence of pulmonary
stenosis (Reversed shunt was initially attributed to overriding of aorta)
• Later found to be due to increased PVR by PAUL
WOOD - Case series of 127 cases
• Because of diversity of anatomical defects that
could lead to EC, he termed it “Eisenmenger
syndrome”

5. First Definition
• Dr Paul Wood
• “Pulmonary hypertension due to a high
pulmonary vascular resistance with
reversed or bidirectional flow at
aortopulmonary, ventricular, or atrial
level”
• This definition still stands today

6. • 1958  Paul Wood who defined ES as
‘pulmonary hypertension at systemic level,
due to a high pulmonary vascular resistance
(>800 dynes/cm5) ( >10 Wood unit × m2),
with reversed or bidirectional shunt through
any large communication between the two
circulations’ (Paul Wood, Br Med J, 1958)

7. Epidemiology
• Incidence of ES has sharply
fallen especially in the
Western world by 50% in the
last 5 decades
• 15-20% of all CHD develop
PAH
– A UK registry between 2001-
2006 showed that 31% of CHD
with PAH developed ES

8. Causes
Pre tricuspid shunt lesions
• –ASD
– ostium secondum - Ostium primum
– Sinus venosus – Tapvc/papvc
Post tricuspid shunt lesions
• –VSD – PDA
• –AP window
Complex CCHD
• –Complete AVSD – TGA with VSD/PDA
• –Truncus arteriosus – Single ventricle physiology
with uninterrupted pbf

9. CHDs developing ES

10. EISENMENGER –AN INDIAN SCENARIO
• Study done from 1976-92 in sct tvm
• 201 Pts with ES
• Mean age of presentation 19yr
• Anatomic lesion most common VSD(33.3%),
ASD(29.85%), PDA (14.3%)
• SCD (30%), CHF(25%) & HAEMOPTYSIS(15%)
• 5YR, 10YR, 15YR SURVIVAL was 86.95%, 79.6% & 76.9%
Prognosis for patients with Eisenmenger syndrome of various aetiology
Saha; International journal of cardiology,vol45,issue 3July 1994, Pages 199–
207

11. Pathophysiology

12. Factors favouring ES
1. Failure of regression of thickened muscular
arteries which are present in fetus
2. Persistence of long densely packed elastic
fibres in large pulmonary arteries resembling
aorta

13. Pathophysiology at cellular level
• Increase in PBF and pressure induce
– endothelial cell dysfunction,
– imbalance between vasodilators and constrictors
• unfavorable vascular remodeling

14. •
Imbalance b/w vasoconstrictor & vasodilators
Endothelins,thromboxaneA2 vs prostacycline, NO
Pathology of pulmonary hypertension Progress in Pediatric
Cardiology 12 (2001). 223-247

15. Heath-Edwards Histopathological
Classification of PH
• GRADE I –Medial hypertrophy in small PA
• GRADE II –Medial hypetrophy + intimal proliferation
• GRADE III-Progressive intimal fibrosis + lumen
occlusion of smaller PA
• GRADE IV- Plexiform lesions in muscular arteries &
plexiform capillary channels
• GRADE V –Complex plexiform + angiomatosis &
cavernous lesions
• GRADE VI-Necrotizing arteritis & fibrinoid necrosis
- UPTO GRADE III CHANGES ARE REVERSIBLE

18. Clinical classification of PAH CHD
• A) Eisenmenger syndrome
• Includes all large intra- and extra-cardiac defects which begin as
systemic-to pulmonary shunts and progress over time to a
severe rise in PVR and shunt reversal (pulmonary-to-systemic) or
bidirectional shunting; cyanosis, secondary erythrocytosis, and
multiple organ involvement is typical
• B) PAH associated with prevalent systemic-to-pulmonary
shunts
• Moderate to large defects with PVR mildly to moderately
increased. There is systemic-to-pulmonary shunting and no
cyanosis at rest. The defect can be a:
– Correctable defect: with surgery or percutaneous procedure;
– Non-correctable defect: PVR is too high

19. • C) PAH with small/coincidental defects
• Marked elevation in PVR in the presence of
small cardiac defects (e.g. ventricular septal
defects <1 cm and atrial septal defects <2 cm
in effective diameter assessed on
echocardiography) which do not account for
the elevated PVR; the clinical picture is similar
to idiopathic PAH
• D) PAH after defect correction
• Congenital heart disease is repaired, but PAH
either persists, recurs or develops
immediately or months/ years after
correction, in the absence of significant
residual haemodynamic lesions

21. Types of Presentation
1) CHF DURING INFANCY & CYANOSIS LATER
(POSTTRICUSPID SHUNT)
• After postnatal fall in pvr  increased pbf
(CCF symptoms but no cyanosis) pulmonary
vascular disease  symptoms
improve,murmur decrease,no cyanosis 
suprasystemic pulmonary pressure causing
rt. to lt. shunt cyanosis, reappearance of
murmur symptoms

22. 2)low Level Symptoms During Childhood & PAH
In Adulthood
–Asymptomatic In Childhood & symptoms Like
Fatigue Cyanosis In Adulthood
–Pretricuspid Shunt
3) Cyanosis From Beginning
–Seen In Complex CCHD

23. WHY EARLY ES IN POSTTRICUSPID
SHUNT THAN ASD?
POST TRICUSPID SHUNT (VSD/PDA)
• PVR never comes down to normal due
to high pressure flow from infancy
• Regression of medial hypertrophy of
smc & RVH does not occur
• Develop PAH & reversal of shunt at an
early age
PRETRICUSPID SHUNTS( ASD)
• Direction of shunt is determined by
the Right ventricular compliance so
no shunt occurs till 3 months
• PVR reaches normal by 3 mths
• PAH & ES occurs late in life especially
in a large ASD
• PAH in ASD believed to be acquired or
unrelated to the defect

24. Clinical features
SYMPTOM FREQUENCY
D.O.E 84%
INCREASED CYANOSIS 59%
HYPERVISCOSITY 39%
ANGINA 13%
SYNCOPE 10%
CHF 8%
Eisenmenger syndrome Factors relating to deterioration and death L. DalientoET
ALEuropean Heart Journal (1998) 19, 1845–1855

25. COMPLICATION FREQUENCY
1. HAEMOPTYSIS 20%
2. PULMONARY
THROMBOEMBOLISM
13%
3. STROKE 8%
4. CEREBRAL ABSCESS 4%
5. I.E. 3%

26. CVS Findings
• Central cyanosis (differential cyanosis in PDA)
• Clubbing
• JVP-dominant a wave/ v wave (TR)
• Precordial palpation- RV heave
• Loud P2
• High-pitched EDM (Graham steel) of PR
• All shunt murmurs disappear

27. DIFFERENTIAL DIAGNOSIS OF ES
ASD VSD PDA
Frequency 1.5 3 2
SEX 1:3 1:1 1:2
DOE GRADE 3 GRADE 2 GRADE 2
ONSET LATE EARLY EARLY
C/C/P 75% 90% 30%
DIFF. CYANOSIS - - +
LARGE A/V WAVE 1/3 RARE UNUSUAL
RV HEAVE + SLIGHT/MODERATE SLIGHT/MODERATE
S2 SPLIT CLOSE SPLIT CLOSE SPLIT
ECG P PULMONALE COMMON LESS COMMON UNUSUAL
RVH 2/3RD 1/3RD 1/3RD
RAE 60% 15% 15%
RT SIDED AORTIC
ARCH
- 16% -
AORTIC KNUCKLE - SEEN SEEN

28. Complications
• HAEMATOLOGY
– Chronic hypoxia causes erythrocytosis & secondary
polycythemia
– Increased iron utilization causes iron deficiency and
microcytosis and hypochromia
– Increased erythrocytes & increased hematocrit–
hyperviscosity
• HAEMOPTYSIS
– Pulmonary artery thrombosis causing pulmonary
infarction
– Thrombocytopenia & decreased coagulation factors

29. • VASCULAR SYSTEM
– Hyperviscosity leads to shear stress causing
release of NO– vasodilation & syncope
• CORONARY CIRCULATION
– Increased NO causes– tortuous & large arteries
• HYPERBILIRUBINEMIA
– Increased erythrocytosis causes increased RBC
destruction– unconjugated hyperbilirubinemia &
gall stones

30. • RENAL DYSFUNCTION
– Hyperuricemia
– Hypoperfusion
• CEREBROVASCULAR EVENTS
– Stroke or TIA– hyper viscosity
– Brain abcess
– Paradoxical embolism-Rt. to Lt. shunting
• CLUBBING-
– Systemic venous megakaryocytes are shunted into the systemic
arterial circulation
– PDGF & TGF-beta released promote cell proliferation, protein
synthesis, connective tissue formation & deposition of extracellular
matrix
• HEART FAILURE
- RV failure

31. Pregnancy & ES
• Pregnancy is contraindicated in ES
• Dual contraception is advised
• EFFECTS OF PREGNANCY ON EISENMENGER
–Increase in blood volume-compromised RV
may not compensate
–Fall in SVR may cause increase in right to left
shunt
–Hypercoagubility during pregnancy- risk of
DVT, pulmonary infarction, stroke

32. Fetal complications
–IUGR
–Premature delivery
• MATERNAL COMPLICATIONS
–Sudden Cardiac Death
–Heart Failure (RV)
–Thromboembolism
–Arrythmia

33. Investigations
• ECG-
• P pulmonale
• RAE,RVH
• KATZ-WACHTEL – equiphasic QRS complexes in
precordial leads – VSD
• Flutter waves – seen in ASD
• Increased RV VOLTAGES, QRS DURN. & QTc interval are
poor prognostic markers

34. Chest X-ray
• Pulmonary oligemia
• Peripheral pruning
• Cardio megaly
• Dilatation of MPA
• Rt sided aortic arch –16% of VSD ES
• “Pulmonary neovascularization” - specific sign for
eisenmenger’s
– Distinctive vascular lesions
– Correlated histologically with collateral vessels

35. Echo
• Very useful for diagnosis
• CW of TR velocity + other echo signs of PH
• other echo signs of PH –
– PR velocity
– Dilated PA
– Dilated RA
– RV outflow doppler midsystolic notching
– RV/LV basal diameter ratio >1
– Flattening of IV septum

36. • Defines the defect (PDA may be difficult)
• Estimates PA pressure by TR/PR jets
• Contrast echo demonstrates RL shunting
• TEE is safe and may be required in adults for
precise delineation of the abnormality

37. Echo Predictors
• A composite score based on the echocardiographic
predictors of outcome:
– TAPSE <15 mm
– Ratio of right ventricular systolic to diastolic
duration> 1.5
– RA area > 25 cm2
– Ratio of RA to left atrial area> 1.5
• This score was strongly related to mortality
• Additional finding was BNP was strongly associated
with mortality
Echocardiographic Predictors of Outcome in Eisenmenger Syndrome Pamela Moceri et
al Circulation. 2012;126:1461-1468

38. Cardiac Cath
• Cardiac cath can be safely performed
• It must be done in borderline cases to assess
operability
• Response of pulmonary vasculature to
pulmonary vasodilators like O2, tolazoline and
nitric oxide should be assessed
• Limit the use of contrast agent to minimal

39. • European guidelines
– <4 WU m2 - closure
– 4-8 WU m2 – grey zone
– >8 WU m2 – No closure
• American guidelines
• R to L shunt where PVR >2/3rd SVR and/or
PASP>2/3rd systemic pressure

40. Management
1. Conventional management
2. Targeted therapy
3. Surgical therapy

41. Conventional management
• Avoid-
– Non cardiac surgery
– Dehydration
– Lung infection
– High altitudes
– Strenuous exercise
– Pregnancy (Dual contraception)

42. O2 therapy
• Long-term home O2 therapy may improve
symptoms
• Recommended in pt. with improvement in
saturation & symptoms with O2 (ESC 2a)
• No survival benefit with nocturnal O2 therapy
in advanced ES

43. Phlebotomy
• Symptomatic hyper viscosity (PCV >0.65)
(ESC 2a & AHA class I)
• Phlebotomy may result in iron deficiency
anemia and cerebrovascular accidents
• Routine phlebotomies -not recommended
(CLASS III AHA )

44. Iron supplements
• Oral iron frequently results in a rapid and
dramatic increase in red cell mass
• Haematological parameters to be monitored
regularly
• Iron therapy stopped once serum ferritin and/
or transferrin saturation within normal range
• Iron intolerant pt – pulse IV iron therapy

45. Oral anticoagulant
• Controversial
• A high incidence of PA thrombosis & stroke vs
high incidence of bleeding & haemoptysis
• In the absence of significant haemoptysis, oral
anticoagulant treatment should be considered
in patients with PA thrombosis or signs of
heart failure (ESC IIA level c)

46. Mx of Hemoptysis
• General measures
– Hospital admission -Reduction of physical activity and suppression of
nonproductive cough
– Chest x-ray followed by CT thorax
– Immediate discontinuation of aspirin, NSAID, anticoagulant
– Treatment of hypovolemia and anemia
• Specific measures
– PLATELET INFUSION
– FFP, vitamin K or coagulation factors
– Angiography with selective embolization of the artery supplying the source
of blood loss
– Sputum culture and treatment of infectious disease
• Risk reduction strategy:
–Immediate treatment of respiratory tract infections
–annual flu vaccination

47. Infective Endocarditis
–High risk for endocarditis with high morbidity and mortality
–Require endocarditis prophylaxis & proper oral hygiene must
be emphasized to prevent endocarditis
Renal dysfunction
–poor prognostic indicator
–volume depletion & NSAID to be avoided
Gout
–Colchicine drug of choice
–Diuretics may trigger it
–Allopurinol & probenecid indicated in recurrent gout
–Poor prognostic marker
Cholecystitis
–Due to gall stones
–ERCP + PAPPILOTOMY RX of choice

48. CCB
• No clear data support the use of CCBs in
patients with Eisenmenger Syndrome
• The empirical use of CCBs is dangerous and
should be avoided (esc class III)

49. Targeted therapy
1. Phosphodiesterase-5 inhibitors: Sildenafil
(viagra, caverta 25mg), Tadalafil (tadacip
10mg, pulmopress 20mg)
2. Endothelin receptor antagonists: Bosentan
(Bosentas 62.5 mg, 125mg), Ambrisentan
(ambrican, endobloc, pulmonext 5mg)
3. cGMP stimulator : Riociguat (Riopah 0.5mg)
4. Prostanoids: Epoprostenol, Treprostinil
infusion, Iloprost inhalation

51. Sildenafil
• PDE5 inhibitor block the enzyme responsible for
degradation of cGMP, secondary messenger for NO
• Reduces PVR, mean PA pressures, increases 6MWD,
SpO2
• STARTS 1 study showed improved functional class &
hemodynamics with medium to high grade dose
• STARTS 2 study showed decreased survival with high
dose sildenafil
• Sildenafil in pediatric PAH not FDA approved
• Sildenafil 0.2-0.3 mg/kg 6-8 hrly
Tadalafil 40 mg daily adult

52. Bosentan
• Target the receptors of ET 1, inhibiting its
vasoconstrictor effects on pulmonary vasculature
• BREATHE-5 trial showed improved hemodynamics,
exercise capacity & functional class
• Small trials showed efficacy of ambrisentan, sitaxentan
in pediatric PAH CHD subgroup
• Macitentan MAESTRO trial – decreased PVR, BNP levels
• Bosentan(non selective)1 mg/kg BD
Ambrisentan(selective) 5 mg OD/in divided doses adult

53. Riociguat
• Soluble cGMP stimulator
• Shown promising effects in adults
• Rioteph 0.5mg, riopah 0.5mg

54. Prostacycline analogues
• IV prostacycline after 1 year of treatment
improved mean PA pressure, PVR, cardiac
index, exercise capacity, NYHA class
• Oral beraprost & inhaled iloprost are shown to
improve hemodynamics in short term, but
long term data are lacking
• Central lines expose the patients to the risk
Of paradoxical embolism and sepsis

55. Combination therapy
• Limited studies
• Does not improve exercise capacity
• Though, improves SpO2

56. Surgical therapy
• Transplantation
1. 1982 : Combined heart-lung transplantation introduced
by Reitz et al
2. 1990 : Single lung transplantation with repair of cardiac
defect successfully performed by Fremeset al
• Lung transplant has advantages of
1. better donor availability
2. Avoidance of cardiac allograft rejection
• Heart lung transplant vs Bilateral lung transplant & shunt
closure vs Single lung transplant (INTERMACS class </= 3)
• “Treat-repair-treat” / “Treat to close” – Not supported by
available data

57. Natural history
ASD PAH
VSD PAH
Pulmonary arterial
hypertension in adults born
with a heart septal defect: the
Euro Heart Survey on adult
congenital heart disease Heart
2007;93:682–687

58. CAUSES OF DEATH IN ES
• 1998 Daliento et al study
 Sudden death 29%
 RV failure 23%
 Hemoptysis 11%
 Post pregnancy 5%
 Cerebral abscess 3%
 Infective endocarditis 1.6%

59. PREDICTORS OF MORTALITY IN ES
1. Low Hb
2. Low NYHA/WHO Functional class
3. Heart failure-clinical & lab ( impaired LFT)
4. Recent change in NYHA class
5. Recently increased antiarrythmic/diuretic dose
6. ECG features- Increased QRS duration, QTc
7. H/o arrythmia
8. Complex CHD
9. Low s. albumin
10. Low K+
11. Pregnancy
12. Lv Dysfunction
13. Syncope
EHJ, July 2006

60. SURVIVAL IN EISENMENGER
SYNDROME PATIENTS

61. • Life expectancy reduced by about 20 years
• Survival Pattern:
1. At one year 97%
2. At 5 years 87%
3. At 10 years 80%
4. At 15 years 77%
5. At 25 years 42%
• In IPAH 3YR SURVIVAL < 20 –30%
• Superior survival seen vs IPAH
– RV dysfunction occurs late
– Rt to left shunt maintains the cardiac output

62. Summary
• Eisenmenger is a preventable disease
• Survival better than IPAH
• Targeted therapies are found to be effective
• Pregnancy is contraindicated in ES
• Heart lung transplantation - “Prevention is
better than cure”