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Eisenmenger syndrome is an end-stage complication of congenital heart disease that occurs when a left to right shunt causes pulmonary over-circulation, leading to vascular remodeling, increased vascular resistance, and ultimately even shunt reversal. Aside from cardiac complications, this pathology has unique complications secondary to chronic cyanosis. In this episode of CardioNerds co-founder Dr. Amit Goyal, ACHD series co-chair Dr. Josh Saef, and Dr. Khaled Tuwairqi (ACHD cardiologist at King Faisal / Elite Hospitals) join Dr. Alexander (Sasha) Optowsky (Director of the Adult Congenital Heart Disease Program at Cincinnati Childrens) to discuss diagnosis and management of Eisenmenger syndrome. Show notes were drafted by Dr. Anna Scandinaro and episode audio was edited by CardioNerds Academy Intern Dr. Akiva Rosenzveig.

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The CardioNerds Adult Congenital Heart Disease (ACHD) series provides a comprehensive curriculum to dive deep into the labyrinthine world of congenital heart disease with the aim of empowering every CardioNerd to help improve the lives of people living with congenital heart disease. This series is multi-institutional collaborative project made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Josh Saef, Dr. Agnes Koczo, and Dr. Dan Clark.

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Pearls – Eisenmenger Syndrome

1. First described in 1897 by Victor Eisenmenger, Eisenmenger syndrome is a long-term complication of unrepaired left to right shunts, resulting from pulmonary vascular remodeling and pulmonary hypertension. This eventually leads to reversal of the shunt, with right to left flow causing cyanosis.
2. Evaluation for Eisenmenger syndrome should include a comprehensive history, physical exam, ECG, echocardiogram, cardiac catheterization, and laboratory work to identify multi-system complications of cyanosis and secondary erythrocytosis.
3. The most definitive means to diagnose Eisenmenger syndrome in a patient with a prior left-to-right shunt lesion is with a right heart cardiac catheterization showing right to left shunting (Qp:Qs < 1).
4. Eisenmenger syndrome is a multi-organ disease and many manifestations occur due to secondary erythrocytosis. Prevention and treatment of these complications are the major goals of care in this population. Complications of Eisenmenger syndrome include gout, bilirubin gallstones, stroke, paraganglioma/pheochromocytoma, thrombophilia, retinal changes, hypertrophic osteoarthropathy, and kyphoscoliosis.
5. Emergency non-cardiac complications of Eisenmenger syndrome include cerebral abscess and hemoptysis.
6. Pregnancy is contraindicated in Eisenmenger syndrome due to high maternal and fetal mortality.

Notes- Eisenmenger Syndrome

1. How does Eisenmenger syndrome develop? Does everyone with a left-to-right shunt develop it? Can it develop as an iatrogenic complication?

The pulmonary vasculature is not used to seeing the increased flow it receives in the context of a left to right shunt. Over time this leads to an increase in pulmonary vascular resistance and pulmonary hypertension. When pulmonary pressures exceed systemic pressures, this causes shunt reversal with right to left shunting causing deoxygenated blood to cross from right side of the heart to the left side bypassing the lungs and causing cyanosis.

The process of developing Eisenmenger syndrome is chronically progressive and so adaptive changes have time to occur. Not all persons with unrepaired shunts will develop Eisenmenger syndrome and it is not completely understood why these differences exist.

Eisenmenger syndrome can be acquired by the creation of palliative aorto-pulmonary shunts which cause pulmonary over-circulation with elevated PVR. This is less commonly seen now, due to earlier corrective repairs occurring at younger ages instead of palliative repairs with plans to perform corrective repairs at older ages. This could be seen in a patient who had a palliative repair in 1960-1980s and was lost to follow up. Eisenmenger syndrome is uncommon in Blalock-Taussig-Thomas (BTT) shunts (especially classic BTT) due to their small size and relatively limited flow.

2. What must-not miss conditions may mimic Eisenmenger syndrome?

Large vessel obstruction, specifically bilateral pulmonary artery stenosis and double chamber right ventricle (gradient through the RVOT leading to R->L shunt causing cyanosis), may mimic Eisenmenger syndrome. Their management and natural history differ from Eisenmenger syndrome and can be reversed with treatment.

3. How should one initiate a workup for Eisenmenger syndrome?

History – ask about symptoms of dyspnea, decreased exercise tolerance, and cyanosis. It is important to establish a detailed surgical history.

Physical exam – specifically assess for the presence (or absence) of a murmur, loud P2 suggestive of pulmonary hypertension, and differential cyanosis (suggestive of PDA – hint see Episode 263 for more information on PDAs and Eisenmenger syndrome). Additional Pearl: take blood pressure on opposite side of a BTT shunt, as a BTT can affect the BP!

EKG – look for evidence of right ventricular hypertrophy: RAD, RVH.

CXR – may show prominent pulmonary trunk.

Laboratory evaluation – should include CBC, iron panel, uric acid, CMP, and BNP to evaluate for signs of secondary erythrocytosis.

Echocardiogram – define the anatomy, calculate right ventricular systolic pressure, pulmonary artery diastolic pressure from pulmonary regurgitation jet, and flow across RVOT and LVOT for estimate of Qp/Qs.

Cardiac cath – measure pressures and saturations, calculate Qp/Qs, assess response to vasodilator challenge, calculate CO by Fick (not thermodilution assumptions for thermodilution are not met with shunts), and rule out mimics.

Remember: You must have had a right heart cardiac catheterization to diagnose someone with Eisenmenger syndrome. When reviewing external data, it is always important to interpret the primary data yourself to ensure the right diagnosis and management.

4. What are some multi-organ complications that can be seen in Eisenmenger syndrome secondary to cyanosis and secondary erythrocytosis (kidney’s response to cyanosis)?

• Gout due to over production and decreased excretion of uric acid
• Bilirubin gallstones due to high RBC turnover
• Stroke due to paradoxical emboli
• Paraglioma/pheochromocytoma due to mutations in the hypoxia pathway – VHL, succinate dehyrdrogenase, hypoxia inducible factor- curable cause of deterioration, should be investigated for in a patient with Eisenmenger syndrome and hypertension
• Thrombophilia
• Retinal changes
• Hypertrophic osteoarthropathy
• Kyphoscolisosis.

5. What is a life-threatening emergency that should be considered if a patient with Eisenmenger syndrome presents with neurologic symptoms? How about hemoptysis?

In a patient with Eisenmenger syndrome presenting with neurologic symptoms there should be a high index of suspicion for cerebral abscess. Chronic hypoxemia leads to secondary erythrocytosis leading to hyperviscosity in the central venous blood, this causes a favorable environment for bacterial growth.

Hemoptysis is not uncommon in this population and is a life threatening complication of Eisenmenger syndrome which requires a broad but direct differential to treat emergent cases quickly. The differential diagnosis includes pulmonary infections (Eisenmenger syndrome can cause decreased immune function), pulmonary vasoocclusive disease, aorto-pulmonary collaterals, as well as pulmonary artery in-situ thrombosis. Obtaining a Chest CTA is a high yield clinical tool to help establish this diagnosis. Interventional colleagues will be instrumental in treatment of many of these complications. Hemoptysis and iatrogenic surgical death used to be a high cause of mortality; this has decreased in recent years.

6. What steps can be taken to minimize operative risk in patients with Eisenmenger syndrome? Do we use routine phlebotomy in this population?

Surgery should be performed with an experienced cardiac anesthesiologist. Operative risk in Eisenmenger syndrome is lower than in pulmonary arterial hypertension as patients with Eisenmenger syndrome are able to increase their cardiac output by increasing right to left shunting at the expense of their oxygenation. Bubble filters should be used as available to minimize risk of air and paradoxical embolism. For non-urgent operations, exchange transfusions before surgery can improve clotting function.  Coagulations labs are affected by high hematocrit (less plasma = fewer clotting factors); you will need to adjust citrate in the tube for an accurate PT/PTT.

Routine phlebotomy is no longer used in this population in the absence of moderate to severe hyperviscosity symptoms. Instead, the focus has shifted to iron deficiency. Repleting iron can improves symptoms of hyperviscosity, increases exercise capacity, and reduces stroke risk.

7. What is “Treat to Close” and should it be used in Eisenmenger syndrome?

The new area of “Treat to Close” is an evolving area without much data to support its practice. There is a need for randomized clinical trials and further investigation to clarify its use. Indications for shunt closure can be found in the 2018 AHA/ACC and the 2020 ESC Guidelines for the Management of Adults with Congenital Heart Disease. It is contraindicated to close a shunt when Eisenmenger syndrome has developed.

8. Is it safe for someone with Eisenmenger syndrome to become pregnant?

Among the few cardiac conditions where pregnancy is contraindicated are pulmonary arterial hypertension and Eisenmenger syndrome. In a pregnant woman with a resting oxygen saturation of less than 90%, babies are born small for gestational age, and most are born premature. In a pregnant woman with a resting oxygen saturation of less than 85%, less than 10% of babies are born alive. The maternal death rate is approximately 30% in these patients.  Of note, some PAH medications are contraindicated in pregnancy.

9. Do patients with Eisenmenger syndrome receive heart transplants?

Transplantation in Eisenmenger syndrome requires both heart and lung transplant. The number of heart-lung transplant for congenital heart disease is a small proportion and even less so for Eisenmenger syndrome. Transplantation is complicated in patients with Eisenmenger syndrome due to the multi-organ system dysfunction that is often present.

References – Eisenmenger Syndrome

Opotowsky, Alexander R., et al. “Pheochromocytoma and paraganglioma in cyanotic congenital heart disease.” The Journal of Clinical Endocrinology & Metabolism 100.4 (2015): 1325-1334.

Silversides, Candice K., et al. “Pulmonary thrombosis in adults with Eisenmenger syndrome.” Journal of the American College of Cardiology 42.11 (2003): 1982-1987.

Baumgartner, Helmut, et al. “2020 ESC Guidelines for the management of adult congenital heart disease: the Task Force for the management of adult congenital heart disease of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Adult Congenital Heart Disease (ISACHD).” European heart journal 42.6 (2021): 563-645.

Stout, Karen K., et al. “2018 AHA/ACC guideline for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.” Journal of the American College of Cardiology 73.12 (2019): e81-e192.

Regitz-Zagrosek, Vera, et al. “2018 ESC guidelines for the management of cardiovascular diseases during pregnancy: the task force for the management of cardiovascular diseases during pregnancy of the European Society of Cardiology (ESC).” European heart journal 39.34 (2018): 3165-3241.

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