Eisenmenger Syndrome Anita Saxena Department of Cardiology, All India Institute of Medical Sciences New Delhi, India 110029

Eisenmenger Syndrome 1887 : Victor Eisenmenger described history and postmortem details of 32 year old man with VSD and pathological features of PAH

Eisenmenger Syndrome 1958: Paul Wood’s Croonian Lectures coined the term “Eisenmenger Syndrome”

Eisenmenger Syndrome Definition: Pulmonary hypertension at or near systemic level with reversed or bidirectional shunt between the pulmonary and systemic circulation and pulmonary vascular resistance above 800dyn/cm-5 (10 Wood Units) Paul Wood, Br Med J, 1958

Eisenmenger Syndrome Underlying Basic Lesions Type of lesion Somerville ‘98 Daliento et al ‘98 (n=132) (n=188) Ventricular Septal Defect 45 71 Atrial Septal Defect 6 21 Patent ductus arteriosus 12 36 Atrio ventricular septal defect 16 23 Truncus arteriosus 15 11 Single ventricle 13 9 Transposition of great arteries 5 8 Others 20 9

Eisenmenger Syndrome – A progressive disease

Exact mechanism not clear Eisenmenger Syndrome Mechanism of abnormal pulm vascular response Stimulation of insulin like growth factor Impaired relaxation of pulmonary arterioles Increased endothelin production Elevated plasma thromboxane B2 Exact mechanism not clear

Pulmonary Arterial Hypertension Hyperkinetic Obstructive (Eisenmenger’s) Heart Size Large Normal Parasternal impulse Hyperkinetic Forcible Click Absent Present S2 ASD wide & fixed wide & fixed VSD wide & variable Single PDA paradoxic split normal split Shunt murmur present short/absent Flow murmur Present Absent

At what age a large VSD Eisenmengerize? 1 Question 1 At what age a large VSD Eisenmengerize? < 6 months 2 years 10 years 20 years

Eisenmenger Syndrome Clinical Groups Cyanosis since birth: TGA, Truncus, Univentricular hearts Failure to thrive in infancy – A settled phase – Symptomatic adolescent: Large VSD, PDA, AVSD Insidious presentation: AP Window

Eisenmenger Syndrome Clinical Evaluation History of symptoms of L R shunt in infancy Cyanosis, erythrocytosis, headache Mildly symptomatic with dyspnoea, fatigue History of syncope, hemoptysis,CVA

Question 2 ES - Underlying CHD Which one of the following clinical sign is unlikely in VSD ES (uncomplicated) Single S2 Palpable second sound Cardiomegaly Absent parasternal heave

Eisenmenger’s Physiology: Clinical Assessment Cyanosis: generally mild Absence of cardiomegaly, heart failure Minimal left parasternal lift Constant ejection click of PAH Absence of significant shunt murmurs Pulmonary regurgitation murmur may be audible

ES: Underlying CHD Characteristic VSD PDA ASD Usual age of ES < 2 years 20 – 40 years Differential Cyanosis - Yes (50%) Cardiomegaly Yes Second H S (S2) Single Narrow/normal Wide & fixed Parasternal heave TR murmur PR murmur

Noninvasive Assessment

Eisenmenger Syndrome Noninvasive Evaluation Echocardiography is very useful Defines the large 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

Eisenmenger Syndrome: Invasive Evaluation Cardiac cath can be safely performed It must be done in borderline cases to assess operability Response of pulmonary vasculature to pulmonary vasodilators like 02, tolazoline and nitric oxide should be assessed Limit the use of contrast agent to minimal

Eisenmenger Syndrome: Natural history Question 4 Eisenmenger Syndrome: Natural history Identify the false statement Prognosis of ES is good Survival better than IPAH With recent advances, pregnancy better tolerated Heart failure most common cause of death

Eisenmenger Syndrome Natural History Life expectancy reduced by about 20 years Survival Pattern: At one year 97% At 5 years 87% At 10 years 80% At 15 years 77% At 25 years 42%

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Policy of “non-intervention”, unless absolutely necessary Life expectancy reduced by about 20 years Unwarranted surgical closure hastens death Policy of “non-intervention”, unless absolutely necessary Avoid destabilizing the “balanced physiology”

ES – Survival better than IPAH

Landzberg, M. J. et al. J Am Coll Cardiol 2006;47:D33-D36 Impact of left ventricular dysfunction on survival in Eisenmenger syndrome Landzberg, M. J. et al. J Am Coll Cardiol 2006;47:D33-D36

Cumulative mortality rate curve (with 95% CIs) Overall population (n=229) According to functional class Dimopoulos, K. et al. Circulation 2010;121:20-25

Long Term Survival in Eisenmenger physiology Survival prospects of patients with Eisenmenger physiology when compared with an age- and gender-matched healthy population showing reduced life expectancy in patients with Eisenmenger syndrome. The survival curve appears to be shifted leftwards by ∼20 years in patients with simple underlying lesions and ∼40 years in those with complex lesions. †Predicted survival is based on the life tables for UK and Wales (2001–2003 interim life tables) published by the Government Actuary's Department. *Comparison between Eisenmenger patients with simple and complex lesions. Patients with complex lesions had a significantly worse outcome compared with those with simple lesions. Diller G et al. Eur Heart J 2006;27:1737-1742

Eisenmenger Syndrome Predictors of Poor outcome History of syncope Elevated right heart filling pressure Severe hypoxemia (Sa02<85%) Lange RA et al, 1998

Eisenmenger’s Syndrome Is Preventable

Eisenmenger Syndrome Management Strategies Drug treatment Phlebotomy Transplantation : Heart lung / lung Counsel against special risks Pregnancy Hormone contraceptives Noncardiac surgery High altitude/flying Sudden emotional upset 30

Conventional Therapy Digitalis, diuretics Anti-arrhythmic drugs Anticoagulants Long term oxygen therapy Avoidance of dehydration, high altitude, infections and IV lines Avoidance of pregnancy

Targeted Therapy: Pulmonary Vasodilators Prostanoids: Epoprostenol infusion Phosphodiesterase-5 inhibitors: Sildenafil, tadalafil Endothelin receptor antagonists: Bosentan (BREATH-5 trial) Fernandes SM, et al 2003 Chou EM, et al 2007 Mukhopadhyay S, et al 2006 Galie N, et al 2006 Gatzoulis MA, et al 2008

Survival in Eisenmenger Syndrome Patients on Advanced Therapy (n=287) Dimopoulos, K. et al. Circulation 2010;121:20-25

Bosentan in ES

Bosentan in ES: BREATH 5 Gatzoulis MA, Int J Cardio 2008

Eisenmenger Syndrome: Role of Phlebotomy Indication for Isovolumic Phlebotomy Symptomatic hyper viscosity (PCV >0.65, Hb>20gm%) Important issues to remember Symptoms of hyper viscosity resemble those of iron deficiency Phlebotomy may result in iron deficiency anemia and cerebrovascular accidents Discourage routine phlebotomy

Management of Eisenmenger Syndrome Transplantation 1982 : Combined heart-lung transplantation introduced by Reitz et al 1990 : Single lung transplantation with repair of cardiac defect successfully performed by Fremes et al Lung transplant has advantages of better donor availability Avoidance of cardiac allograft rejection Absence of coronary vasculopathy

Management of Eisenmenger Syndrome Lung Transplantation Actuarial survival rates : At 1 year 70-80%, At 4 years <50%, At 10 years <30% Indications for transplant History of syncope Refractory right heart failure Poor exercise tolerance Severe hypoxemia

Perioperative Risk for Noncardiac Surgery High risk conditions Pulm hypertension Cyanotic CHD NYHA class III or IV Severe ventricular dysfuntion (EF<35%) Severe left heart obstructive obstruction Moderate risk conditions Intracardiac shunt lesions ACC/AHA guidelines 2008

Perioperative Risk for Noncardiac Surgery in Eisenmenger Syndrome Associated with a mortality rate of 14% -19% Local anesthesia is preferred to general anesthesia Prolonged fasting and volume depletion should be avoided Small air bubbles in IV lines should be removed Early ambulation is encouraged Antibodies given to prevent infective endocarditis

Pregnancy and congenital heart disease Risk to Fetus: if Sao2 < 85%, chances of live fetus only 12% Caesarian section only for obstetric reasons

Complications During Pregnancy in Women with CHD Drenthen W, et al. Outcome of pregnancy in women with congenital heart disease: a literature review. J Am Coll Cardiol 2007;49:2303-11

Complications During Pregnancy in Women with CHD Drenthen W, et al. Outcome of pregnancy in women with congenital heart disease: a literature review. J Am Coll Cardiol 2007;49:2303-11

Management of Eisenmenger Syndrome Avoidance of Pregnancy Pregnancy is absolutely contraindicated Maternal mortality is 36%-45% Mortality often occurs in post-partum period Fetal loss occurs in over 60% Termination is indicated in early gestation Outcome of pregnant women with Eisenmenger syndrome has not changed in last three decades

Eisenmenger Syndrome Management of Pregnancy Prolonged bed rest after 20th wks gestation Oxygen therapy Digoxin and diuretics if CHF present Prolonged use of anticoagulants - Heparin Careful monitoring of volume status, oxygen saturation and hematocrit is necessary

Eisenmenger Syndrome Basic Events Leading to Death Right ventricular failure 30% Sudden death?vent arrhythmia 25% Cardiovascular surgery 12% Cerebrovascular accidents/abscess 10% Hemoptysis 9-15% Noncardiac surgery 6% Pregnancy related 5% Heart lung/lung transplants 4%

Carefully managed, most patients lead useful lives Eisenmenger Syndrome Is generally established by 2-4 yrs of age Accelerated onset in Down’s, Cyanotic CHD Median survival is 40-45 yrs of age Anesthesia, surgery, dehydration poorly tolerated Pregnancy carries 30-50% maternal mortality Closure of the defect is detrimental once obstructive PAH has developed Carefully managed, most patients lead useful lives

“Doing nothing may be a positive action for Eisenmenger Syndrome Conclusion Patients with Eisenmenger syndrome can live upto fifth and sixth decades with informed medical care, patient education and protection from special risks 20% of death are related to avoidable errors “Doing nothing may be a positive action for good in such patients” Jane Somerville, 1998