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CardioNerds (Daniel Ambinder), ACHD series co-chair,  Dr. Josh Saef (ACHD fellow at University of Pennsylvania), and ACHD FIT lead Dr. Charlie Jain (Mayo Clinic) join ACHD expert Dr. George Lui (Medical Director of The Adult Congenital Heart Program at Stanford and Program Director for the ACGME adult congenital heart disease fellowship at Stanford) to discuss Tetrology of Fallot. Audio editing by CardioNerds Academy Intern, Dr. Leticia Helms.

Tetralogy of Fallot (ToF) is the most common cyanotic heart disease and one of the most common congenital heart diseases that we see in adults overall. The anatomy includes a ventricular septal defect (VSD), an overriding aorta, and infundibular hypertrophy with subpulmonic +/- pulmonic valvular +/- supravalvular stenosis, which causes severe RV outflow obstruction and subsequent RV hypertrophy. Patients require surgery during childhood, which includes patching the VSD and relieving RV outflow obstruction. This results in pulmonic regurgitation (usually severe) and patients can live with this for decades. Adults with ToF commonly will require pulmonic valve replacement, potential relief of subvalvular or supravalvular stenoses, and tricuspid valve repair (for functional tricuspid regurgitation caused by RV dilation). These patients are at increased risk of atrial and ventricular arrhythmias and may warrant prophylactic ICDs.

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.

The CardioNerds Adult Congenital Heart Disease Series is developed in collaboration with the Adult Congenital Heart Association, The CHiP Network, and Heart University. See more

Disclosures: None

Pearls • Notes • References • Guest Profiles • Production Team

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Pearls – Tetralogy of Fallot

1. Tetralogy of Fallot is the most common cyanotic heart disease and the 4 anatomic features are: VSD, infundibular hypertrophy (with RVOT obstruction), overriding aorta, and RV hypertrophy. The most common lesion you will see in adults with repaired Tetralogy of Fallot is pulmonic regurgitation.
2. Pulmonic regurgitation (PR) can be easy to miss on exam as the murmur is brief and even shorter when the PR is severe. In patients with PR and aortic regurgitation, remember PR is clearest when laying supine, in comparison to aortic regurgitation which is loudest while leaning forward.
3. Patients with ToF may also have coronary anomalies (e.g. LAD off RCA), right-sided aortic arches, and also left-sided heart disease (LV diastolic or systolic dysfunction).
4. Patients with ToF are at risk for atrial and ventricular arrhythmias, and clinicians should consider prophylactic ICD for those with multiple risk factors for sudden death (e.g. QRS >180ms, scar on MRI).
5. In all patients with congenital heart disease, inspection is a key part of the physical exam (e.g. right thoracotomy could clue you into a prior BTT shunt) and in patients with prior BTT shunts and/or prior brachial cut-downs (look in the antecubital fossa for scars), radial arterial access is discouraged.

Show notes – Tetralogy of Fallot

Lesion	TTE	TEE	Cardiac MRI	Cardiac CT
Tetralogy of Fallot	(1) Routine assessment of RV and LV size and function (2) Routine semiquantitative assessment of pulmonic valve regurgitation (3) Evaluation of PVR/conduit gradients, and RV pressure via tricuspid regurgitation gradient (4) Evaluation of proximal aortic dilation, proximal pulmonary artery branch stenosis (5) Identification of residual intracardiac shunts	(1) Intraoperative management (pre- and post- bypass imaging). (2) Comprehensive echocardiographic evaluation when transthoracic windows are limited, and advanced imaging modalities are unavailable.	(1) Quantitative evaluation of PR severity (phase contrast MRI) when echo-derived severity is inconclusive (2) Serial quantitative assessment of RV volume and ejection fraction to evaluate indications for PVR or conduit replacement in patients with pulmonary insufficiency. (3) MR angiography of aorta and pulmonary artery/branches to assess for dilation or stenosis. (4) Quantitative flow assessment of differential pulmonary arterial blood flow in the setting of branch PA stenosis (phase contrast MRI). (5) Late gadolinium enhancement imaging to assess for RV fibrosis in arrhythmia risk stratification.	(1) Can be used for quantitative RV volume and ejection fraction assessment when CMR is contraindicated at expense of ionizing radiation. (2) Detailed evaluation of aortic and pulmonary arterial anatomy. (3) Detailed evaluation of coronary artery anatomy (e.g., relation of coronary artery to RV to PPA conduit prior to percutaneous valve implantation) (4) Evaluation of aortopulmonary collaterals.

1. What is the embryologic origin of Tetrology of Fallot (i.e. anterocephalad deviation of spiral septum)?

With Tetralogy of Fallot, the most important considerations are in the embryology of the primitive outflow tract. 

• In normal anatomy, early in gestation, the outflow tract starts as a hollow tube termed the conotruncus. Neural crest tissue migrates into the tube and forms two major collections of endocardial cushion tissue. The collections develop opposite each other, rotating in a counterclockwise spiral through the entire conotruncus. These cushions then grow into balanced left and right ventricular outflow tracts and fuse with the interventricular septum inferiorly.
• In ToF, there is 1) anterocephalad deviation of the muscular outlet septum which causes a large interventricular communication (i.e. VSD) to form underneath the aortic valve, and 2) abnormal arrangement of the septoparietal trabeculations. These 2 abnormalities cause RV outflow obstruction and subsequent RV hypertrophy.¹ There can be a wide spectrum of disease from isolated subpulmonic obstruction with a relatively small VSD to a large VSD with near pulmonary valve atresia.
• Most patients with Tetralogy do not have an identifiable genetic mutation. However, up to 15% may have some type of genetic syndrome, most commonly 22q11 microdeletion (Velocardiofacial, or DiGeorge syndrome).² This is clinically relevant because 22q11 microdeletion is an autosomal dominant mutation thus impacts pre-conception counseling in patients considering pregnancy.

2. What are the key features of ToF anatomy (e.g. VSD, RVOT obstruction, overriding aorta, RVH)?

• The classic 4 abnormalities originally described by Dr. Fallot in 1888 are 1) RVOT obstruction (always subvalvular +/- valvular/supravalvular), 2) interventricular communication/VSD, 3) aortic override, 4) RV hypertrophy which occurs secondary to the obstruction.
• This is repaired by closure of the VSD, relief of obstructive RVOT muscle, and relief of any potential pulmonic valve or supravalvular stenosis. Commonly the pulmonic annulus is hypoplastic, and traditionally was treated with enlargement with a transannular patch. This causes severe pulmonic regurgitation.
• Associated anomalies include right aortic arch, atrial septal defect, and less commonly AV canal defects.
• Coronary anomalies are common and one of the most common is an anomalous LAD off of the RCA. This is particularly relevant as its course over the RVOT complicates the surgical approach.

3. What are the hemodynamic consequences of the above structural abnormalities (e.g. RVOT obstruction, VSD shunting)?

• Prior to any repair, the RVOT obstruction is dynamic and in ways comparable to hypertrophic cardiomyopathy, but with the twist that is the VSD. “Blue Tets,” or patients who had cyanosis, had significantly decreased pulmonary blood flow from severe RV outflow obstruction and would have worsened symptoms from hypoxemia and low flow by anything that worsened pulmonary blood flow. This would be worsened in situations which caused stress (faster HR, smaller ventricle, more obstruction), hyperventilation and /or hypoxemia (higher pulmonary vascular resistance), or exercise (faster HR and also SVR drops more than PVR). These so called “Tet Spells” could be improved by increasing venous return to the right heart and/or increasing systemic vascular resistance. These can both be achieved by squatting, thus children with unrepaired Tetralogy will do this almost instinctively and in babies with cyanosis during crying the parents will be instructed to bring the babies legs toward the chest.³
• “Pink Tets” on the other hand have relatively mild obstruction to RV outflow and therefore have a lot of VSD flow from LV to the pulmonary vascular tree. This can cause left heart volume overload and CHF early on in life. If this goes uncorrected for a long time, it can predispose to pulmonary vascular disease. “Pink Tets” over time may develop worsened RV outflow obstruction and subsequently become “Blue Tets.”

4. How would an adult with corrected ToF anatomy present (e.g., VT, RV failure, PV endocarditis)?

• As above, the most common lesion in adults with repaired Tetralogy is severe pulmonic regurgitation. While this may be tolerated for decades, pulmonic valve replacement is indicated when the patient has:⁴
  • ≥ moderate PR with symptoms (commonly fatigue, decreased exertional capacity)
  • Asymptomatic but has at least 2 of the following:
    • >mild RV or LV dysfunction
      • Severe RV enlargement (EDVi >160 or ESVI >80 or >2x LVEDV)
      • RVSP >2/3 LVSP
      • Reduction in objective exercise tolerance

• Transcatheter pulmonic valve replacements are being performed in many patients now, both with prior valve replacements (valve-in-valve) and also those with native outflow tracts. These interventions are likely changing the “natural” history of Tetralogy as now patients can avoid more trips to the operating room and the risks and debilitation that come along with it. That being said, patients with concomitant lesions (e.g., severe tricuspid regurgitation, small pulmonic annulus, multilevel RVOT obstruction) may still be best served by surgery.
• All patients with valve disease, particularly those with multiple prosthetic valve interventions are at increased risk of endocarditis. As many patients with ACHD have prostheses starting at a young age, they are at significantly increased risk of endocarditis over their lifetime. Dental hygiene should be discussed at every routine visit.
• Right bundle branch block is ubiquitous in Tetralogy given the septal anatomy and VSD patching.
• Patients with Tetralogy are at increased risk of both atrial and ventricular arrhythmias. Some patients may benefit from prophylactic ICD but we should always address underlying hemodynamic/structural lesions first. Risk factors for sudden death include:
  • QRS >180 ms
  • Multiple prior operations
  • Older age at repair
  • LV dysfunction (potentially even diastolic)^{4, 5}

• ICDs are not benign! Inappropriate shocks are not uncommon and given the young age at which they are placed, patients are at increased risk for device infections over their lifetime.
• Aortic root dilation is seen in 30-50% of patients, though rarely (<5% patients) does this require intervention.^{4, 6}

5. What makes your heart flutter about ACHD?

• Every patient is a history lesson! We learn a lot from our patients and every day are humbled by all they have gone through.
• There is a wide spectrum of presentation of each disease! Some patients with Tetralogy will have complicated surgical history such as the one presented here whereas others may go their whole life with only one or two surgeries! For example, Olympic and X-Games champion snowboarder Shaun White has Tetralogy of Fallot!
• It is an incredible interplay of anatomy and physiology. Every day we are challenged to apply what we know from acquired heart disease to our patient with unique anatomy and think about whether or not the fundamentals we usually rely on hold true here. For instance, patients with severe pulmonic regurgitation may have unimpressive murmurs because of the rapid equalization of PA and RV pressures. On echocardiography, the jet can be very rapid on color and CW Doppler and may even be called trivial by someone not familiar with looking at severe PR. We always have to be on our toes and think critically for our patients.
• ACHD incorporates all fields of cardiology – imaging, heart failure, electrophysiology, interventional, etc… and we have opportunities to be involved with all of these subspecialties – doing TEEs, hemodynamic catheterizations, caring for patients in the ICU. Furthermore, we work closely with surgeons and care closely for post-operative patients.

References

1.         Anderson RH, Spicer DE, Giroud JM, Mohun TJ. Tetralogy of Fallot: nosological, morphological, and morphogenetic considerations. Cardiol Young. Dec 2013;23(6):858-66. doi:10.1017/S1047951113001686

2.         Beauchesne LM, Warnes CA, Connolly HM, et al. Prevalence and clinical manifestations of 22q11.2 microdeletion in adults with selected conotruncal anomalies. J Am Coll Cardiol. Feb 15 2005;45(4):595-8. doi:10.1016/j.jacc.2004.10.056

3.         Kothari SS. Mechanism of cyanotic spells in tetralogy of Fallot–the missing link? Int J Cardiol. Oct 1992;37(1):1-5. doi:10.1016/0167-5273(92)90125-m

4.         Stout KK, Daniels CJ, Aboulhosn JA, 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. Circulation. Apr 2 2019;139(14):e698-e800. doi:10.1161/CIR.0000000000000603

5.         Khairy P, Aboulhosn J, Gurvitz MZ, et al. Arrhythmia burden in adults with surgically repaired tetralogy of Fallot: a multi-institutional study. Circulation. Aug 31 2010;122(9):868-75. doi:10.1161/CIRCULATIONAHA.109.928481

6.         Mongeon FP, Gurvitz MZ, Broberg CS, et al. Aortic root dilatation in adults with surgically repaired tetralogy of fallot: a multicenter cross-sectional study. Circulation. Jan 15 2013;127(2):172-9. doi:10.1161/CIRCULATIONAHA.112.129585

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