Authors

• Irena Ivanac — University of Zagreb School of Medicine, University Hospital Centre Zagreb, Zagreb, Croatia
• Vranešić — University of Zagreb School of Medicine, University Hospital Centre Zagreb, Zagreb, Croatia — ORCID: 0000-0002-6910-9720
• Maja Strozzi — University of Zagreb School of Medicine, University Hospital Centre Zagreb, Zagreb, Croatia — ORCID: 0000-0003-4596-8261

Abstract

Patients with repaired tetralogy of Fallot (ToF), due to the development of complications in adulthood, need to attend regular follow-up at a tertiary adult congenital heart disease (ACHD) center. If disease progression is stable, the follow-up visits are most often indicated on a yearly basis. In addition to a detailed history of symptoms development, it is important to always look for possible complications. In case of a significant pulmonary regurgitation (PR), which is the most frequent late complication of repaired ToF, it needs to be quantified, and changes in right ventricular (RV) size and function need to be monitored. It is important not to postpone the re-intervention on the pulmonary valve (PV) for too long in order to preserve the RV function. It is also important to bear in mind the possible faster progression of prosthesis dysfunction if the operation was done at an earlier age. Since repaired ToF patients belong to the group of ACHD conditions with the highest risk of sudden cardiac death (SCD), it is necessary to stratify their risk by using currently available methods and to consider whether there are any indications for the implantation of a cardioverter defibrillator. In addition to the above, during each follow-up it is necessary to search for all other possible complications in order to better and more comprehensively monitor and treat these patients.

Keywords

tetralogy of Fallot, complications, pulmonary regurgitation, ventricular tachycardia, adult congenital heart disease

DOI

Full Text

## Case report A 23-year-old female was admitted for elective diagnostic follow-up. At the age of 2, the patient had undergone a total tetralogy of Fallot (ToF) repair and had been regularly attending follow-up visits by her pediatric cardiologist and was asymptomatic the entire time. During the latest pediatric follow-up, the echocardiogram reported a mild residual pulmonary valve stenosis (PS) with a maximal systolic pressure gradient (PG) of 20 mmHg, mild pulmonary regurgitation (PR), a mildly enlarged right ventricle (RV), minimal tricuspid regurgitation (TR) and no residual ventricular septal defect (VSD). During the first follow-up by an adult cardiologist echocardiogram still showed a mild residual PS with a maximal systolic PG of 30 mmHg; PR was not mentioned (retroactively, through detailed analysis of the digitally stored echocardiogram, it has been established that PR existed, but as the later text emphasizes, echocardiographic assessment of PR is very complex and is easily underestimated). Also noted was the hypertrophic and mildly dilated RV (end-diastolic RV area of 30 cm2) with preserved systolic function (TAPSE 20 mm), as well as mild TR. During a 24-hour Holter ECG no significant rhythm disturbances were noted. After one year, the patient has come to a follow-up by a cardiologist from the adult congenital heart disease (ACHD) team. She was still asymptomatic, and among the clinical findings a systolic murmur 2-3/6 with punctum maximum above the pulmonary valve was observed. A sinus rhythm with a heart rate of 83/min, right bundle branch block (QRS length of 142 ms) and QTc duration of 454 ms was identified on the ECG. During the follow-up 24-hour Holter ECG, two episodes of ventricular tachycardia (VT) were noticed with a frequency of 150-180/min lasting 10 seconds whose source, judging by the appearance of the QRS, was most likely in the right ventricular outflow tract (RVOT). Echocardiographic follow-up indicated a dilated (diastolic RV area of 34.7 cm2), volume-overloaded RV with a diastolic septal shift to the left and still preserved RV systolic function according to FAC (fractional area change) of 50% and a tricuspid annular plane systolic excursion (TAPSE) of 22 mm, but with reduced s‘ to 7.6 m/s. A significant (probably severe) PR was noted (**Figure 1** and **Figure 2**; PHT of 87 ms, time without flow during diastole was 150 ms, present PA reverse flow, regurgitation jet occupied 60% of the RVOT width, and VC was 0.6 cm) while the maximum systolic PG across the pulmonary valve (PV) was 20 mmHg. A mild TR and the maximal RV systolic pressure of 44 mmHg were noted. The ascending aorta was borderline enlarged to 3.7 cm, without the presence of aortic regurgitation, and the left ventricle (LV) was normal in size and function and no visible VSD was noticed. Considering the non-sustained VT in the asymptomatic patient, a therapy with sotalol was started in a dosage of 2×20 mg. Follow-up 24-hour Holter ECG after 6 days showed no ectopic ventricular activity. Cardiopulmonary exercise testing was performed as well, but it was stopped in the 6th minute because of maximal workload achieved with a satisfactory maximal oxygen uptake of 31 ml/kg/min, a normal increase in arterial pressure and pulse, and without the occurrence of arrhythmia. In the subsequent follow-up period cardiovascular magnetic resonance (CMR) imaging was conducted in another institution. CMR indicated the following: LV of normal size and preserved systolic function, no VSD, normal morphology of the large blood vessels, dilated and trabeculated RV (EDVI of 145 ml/m2, ESVI of 69.1 ml/m2) with normal wall thickness and maintained global systolic function (ejection fraction of RV was 44%). CMR also showed a normal morphology of the PV with a slightly accelerated flow across the valve which was marked as moderate PS. A PR of grade 2+ was found as well. The examination showed a dilated ascending aorta at the aortic root level of 4.0 cm, and LGE showed a punctiform area of imbibition in the middle third of the RV anterior wall, which was concluded not to represent an arrhythmogenic substrate considering its dimensions. Bearing in mind all the above and especially the RV size estimated by CMR, for now we have decided to monitor the patient and to repeat the CMR in the follow-up period to better assess the severity of PR and possible progression of the RV dilation and dysfunction, and to better evaluate all other cardiovascular structures. We have decided to present this case because it is an example of a typical patient with a repaired ToF and problems that can occur in adulthood, which will be addressed in the section below. Figure 1. Continuous wave Doppler across the pulmonary valve showing severe pulmonary regurgitation. Figure 2. Color Doppler and pulsed wave Doppler with the sample volume in the pulmonary artery showing reversed flow in the pulmonary artery during diastole. Several questions were left unanswered in this case and will require an answer during further follow up. They include a more precise quantification of PR, determination of optimal timing for PV surgery, the question of possible peripheral pulmonary artery stenosis, the question of further diagnostics and treatment of VT (whether we should continue with the antiarrhythmic therapy, conduct an electrophysiological study, or just monitor and determine whether there are indications for a cardioverter defibrillator), and others. What we wanted to emphasize with this case report is the need for better education of all cardiologists, both adult and pediatric specialists as well as radiologists (primarily those who perform CMR), about the specificities of adult patients with congenital heart diseases (CHD) as those will be ever more numerous in everyday cardiology practice. Finally, these patients should be referred to tertiary ACHD centers where they will be monitored and treated by a team consisting of cardiologists, cardiac surgeons, radiologists, and other specialists dedicated to this group of patients. ## Literature review Tetralogy of Fallot is the most common cyanotic CHD (1). The incidence is around 10% of all CHD, and the rate of survival to adulthood is greater than 85%. In addition to VSD, overriding aorta, PV/RVOT stenosis (with possible PA stenosis at the level of the trunk, bifurcation or distal branches) and resulting RV hypertrophy, additional anomalies in the structure of the heart and large blood vessels can be present, like atrial septal defect, persistent foramen ovale, right-sided aortic arch (in 25% of the cases), anomalies of the coronary arteries (in 5% of the cases), persistent ductus arteriosus, and others. This is why it is important to look for any other accompanying defects in all patients with ToF. During childhood and before total repair, many of these patients required palliative surgery creating a systemic-pulmonary shunt in order to increase the flow in the pulmonary circulation, which is important to note during the evaluation of the adult patient. Total repair includes VSD closure and relief of RVOT obstruction with resection of the infundibulum and pulmonary valvotomy. Many patients require an additional RVOT or transannular patch, which is considered one of the main causes of postoperative PR and which is one of the main problems in adults with repaired ToF. Other possible complications that can occur in adulthood are residual RVOT obstruction, RV dilation and dysfunction, residual VSD at patch location, dilation of the aortic root with the resulting aortic regurgitation (AR), dysfunction of the LV, atrial and ventricular arrhythmias, sudden cardiac death (SCD) and endocarditis, which occurs rarely. Because of all these potential issues which all require close monitoring, further diagnostics and timely treatment, these patients should attend regular follow-up at a tertiary ACHD center in order to receive optimal medical care. Pulmonary regurgitation is one of the most frequent problems in adult patients after ToF repair and is often clinically significant (whether it is moderate or severe), and requires reoperation. It is the consequence of the previous surgery performed in childhood, which includes pulmonary valvotomy and transannular incision and patch. Adult cardiologists, who are not sufficiently familiar with the problems of patients with ToF, can often overlook PR during echocardiographic imaging because the incidence of PV pathology in general adult population is low, and the optimal imaging of PV is not always possible. An additional reason for misinterpretation of PR severity could be still insufficiently defined echocardiographic assessment of the PR severity. According to the latest recommendations (2) of the European Association for Cardiovascular Imaging, the severity of PR is usually estimated through qualitative methods where severe PR is indicated by parameters such as dense Doppler signal of regurgitation jet with continuous wave Doppler imaging, presence of reversed flow in PA, short PHT (80 ms), and other semi-quantitative parameters such as the regurgitation jet with in RVOT (>65%) or VC, which have not yet been sufficiently validated. Quantitative parameters such as regurgitation volume, regurgitation fraction, and effective regurgitant orifice area (EROA) have also not been validated. However, the first indicators of severe PR could be the signs of RV volume overload (dilated RV and diastolic leftward shift of the interventricular septum). An assessment of the RV size and function is therefore necessary for every patient with PR, using all available echocardiographic methods and parameters usually used in adult cardiology (FAC, TAPSE, TDI s’, and others). In these patients, longitudinal 2D strain is reduced and correlates with RV dilation and the PR severity. The severity of the regurgitation and its effect on the RV are increased with the simultaneous presence of distal PA stenosis or the existence of pulmonary arterial hypertension. Considering the reduced echocardiographic capabilities of precise quantification of the PR severity, it is necessary to integrate all these parameters in order to achieve an insight into the real severity of PR as much as possible. CMR imaging is the gold standard for the assessment of the PR severity as well as for the RV size and function. The most reliable parameter for the assessment of PR is the regurgitation fraction (RF >40% = severe PR). The RV size (end-diastolic volume index >170 ml/m2 and end-systolic volume index>85 ml/m2 indicate a worse prognosis) and function (EF) as well as their change during the follow-up are crucial parameters in the assessment of the appropriate timing for repeated surgical intervention on PV. In addition to the above, CMR is an excellent method for the assessment of LV size and function, the anatomy of the great vessels, RVOT aneurisms, PA and branch stenosis, the assessment of the myocardial scar burden on LGE, for the shunt calculations, etc. Significant PR can be well tolerated for a long time, but after on average 20 years it leads to RV dilation and dysfunction and to the appearance of symptoms of heart failure and arrhythmias, primarily atrial fibrillation, atrial flutter and VT. Initial symptom in these patients can even be SCD, so PR is considered one of the main risk factors for SCD in patients with repaired ToF. It is also known that of all the patients with ACHD, patients with ToF have the greatest risk of developing heart failure. The treatment of PR consists of pulmonary valve replacement (PVR), but the question of the optimal timing for reoperation is still unanswered. According to the guidelines (1) of the European Society of Cardiology (ESC) the progression of RV dilation or dysfunction is considered more important that the absolute values of the stated parameters. Significant RV dilation on CMR (end-diastolic volume index >160 (170) ml/m2 or end-systolic volume index >85 ml/m2) is associated with persistent RV dilation following PVR and a worse prognosis (3). However, surgical procedures at an early age lead to more rapid deterioration of tissue PV and an earlier reoperation or reintervention. Surgical valve replacement is done in most cases with a tissue prosthesis or a homograft. Perioperative mortality is low (around 1%) in patients without advanced ventricular dysfunction or signs of heart failure, and the 10-year survival rate is 92-95%. In adult patients, a second reoperation is needed after 10-15 years on average. In addition to classical surgical procedures, there is also a possibility of percutaneous implantation of the so called “Melody” valve which can be indicated for some patients with PR and a repaired ToF. According to ESC guidelines (1), indication for the PV replacement is a severe symptomatic PR or severe asymptomatic PR if any of the following criteria is present: decrease in objective exercise capacity, progressive TR, progressive RV dilation or dysfunction, RVOT obstruction with systolic RV pressure of >80 mmHg (TR velocity >4.3 m/s) or the presence of sustained atrial or ventricular arrhythmias. Following PVR, regardless of the method, the functional capacity increases and RV decreases in size, but the long-term prognosis and the effect on the survival rate is still unknown. Residual RVOT obstruction can occur at the level of the infundibulum, PV, PA, bifurcation, in the branches of left or right PA (often the result of the previous palliative surgery), and at the conduit anastomoses sites. It impairs the RV function and increases PR in the case of co-existent distal stenosis. Considering the fact that it is often impossible to precisely measure the maximum gradient in RVOT, the most precise echocardiographic assessment of the RV pressure is from the TR velocity acquired from a continuous-wave Doppler imaging. The therapy is a surgical relief of the obstruction or the percutaneous dilation (for example, in the case of the peripheral branch stenosis). Surgical PVR is indicated in cases of severe symptomatic PS (RV systolic pressure >60 mmHg, TR velocity >3.5 m/s) or in case of asymptomatic PS if any of the following criteria are present: decrease in objective exercise capacity, progressive TR, progressive RV dilation or dysfunction, RVOT obstruction with RV systolic pressure >80 mmHg (TR velocity >4.3 m/s) or the presence of a sustained atrial or ventricular arrhythmias. RV dilation and dysfunction can be caused, as described before, by long-term severe PR and/or RVOT obstruction due to the volume or pressure overload but it is also often partly caused by the presence of postoperative myocardial scar formation. One of the causes of RV dysfunction can be dyssynchrony due to the presence of a RBBB, thus for some patients resynchronization therapy (CRT) can be indicated. The consequence of the RV dilation is often significant TR which leads into a vicious cycle of further dilation and deterioration of RV function, and this eventually leads to the development of heart failure and to an increased risk of arrhythmias and SCD. One of the possible problems for adult patients after the repair of ToF can also be a residual VSD due to the patch dehiscence. Most often VSD is small with restrictive flow (high pressure gradient), but if it is significant (Qp:Qs= 1.5:1) then it leads to LV volume overload and development of pulmonary hypertension, and needs to be surgically corrected. VSD closure is also indicated if PV surgery is planned. It is believed that there are multiple causes of LV dysfunction in these patients. Most often mentioned in the literature are long-term cyanosis prior to the operation, volume overload due to long-term palliative arterial shunts, residual VSD or AR, the presence of coronary heart disease, interventricular dependence in the case of severe PR, and others. This problem appears at a later phase of the illness and is a significant prognostic factor for SCD and an adverse clinical outcome. The cause of the aortic root dilation is still not completely clear. It can lead to the development of AR, and a progressive dilation is seen in 15% of the adult patients after repaired ToF. It is believed to be caused by the intrinsic disease of the aorta, as well as by the increased aortic flow (for example in the case of pulmonary atresia) and late repair of the defect. The size of the aorta is usually less than 5 cm and rarely leads to dissection, and is more often present in male patients. Aortic valve replacement is indicated if there is a severe symptomatic AR, or severe asymptomatic AR with the signs of LV dysfunction. Arrhythmias and SCD are one of the most frequent problems in this group of patients. Atrial fibrillation/flutter and ventricular tachycardia can be the consequence of the progressive hemodynamic problems and/or scar formation after the RVOT operation and VSD closure. ToF is one of the ACHD with the greatest risk of SCD of around 2% in the 10-year interval and causes between one third and one half of all late deaths in this population. Some risk factors for SCD are known, such as QRS >180 ms, RV volume overload, LV and RV dysfunction, large areas of ventricular fibrosis on CMR, long-term palliative shunts, VT in the 24-hour Holter ECG, and the clinical and inducible sustained VT. Patients with symptoms (syncope, dizziness, palpitations) require a detailed hemodynamic and electrophysiological evaluation. Asymptomatic patients with non-sustained VT require an individual approach dependent on other clinical characteristics (SCD risk factors). Since there is no clear data, the treatment approach for these patients varies from purely monitoring to antiarrhythmic therapy, electrophysiological study/ablation and implantation of a cardioverter defibrillator (ICD). ICD implantation is definitely indicated in secondary prevention of SCD (sustained VT and after cardiac arrest), but risk stratification in primary SCD prevention is very difficult and there are currently no clear guidelines although there are some suggestions from certain authors (4). While considering the possible implantation of ICD in these usually young persons, one should bear in mind the known possible complications that can occur after the implantation, such as endocarditis or inappropriate device activation and similar complications. According to the latest ESC guidelines (5), ICD implantation should be considered for patients with ToF and multiple SCD risk factors, which include LV dysfunction, non-sustained VT, QRS duration longer than 180 ms, or inducible sustained VT during electrophysiological study. Electrophysiological study can be considered for the SCD risk stratification in patients with ToF who have one or more risk factors such as LV dysfunction, non-sustained VT, and QRS duration longer than 180 ms.

Literature

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