Late presenting tetralogy of Fallot—surgical management

Abstract

Late presentation of tetralogy of Fallot (TOF) poses unique diagnostic and management challenges, differing significantly from those diagnosed and treated in infancy. This review discusses the definition and natural history of late-presenting TOF, emphasizing the surgical and perioperative considerations specific to this population. We also explore the role of phlebotomy in managing polycythemic patients, a practice not universally adopted, and highlight postoperative challenges, including residual defects and complications. While discussing the surgical correction of TOF, we analyse the outcomes of specific strategies and the role of elective pulmonary valve replacement in adult patients. This comprehensive overview aims to shed light on the nuances of managing these complex cases.

Introduction

Tetralogy of Fallot (TOF) is a congenital heart defect comprising four anatomical abnormalities: right ventricular outflow tract (RVOT) obstruction, right ventricular hypertrophy (RVH), ventricular septal defect (VSD), and overriding of aorta, and its prevalence is approximately 1 in 3500 live births and it accounts for 7–10% of all patients with cyanotic congenital heart disease (CHD), making it the commonest form of the latter [1]. It typically manifests shortly after birth with characteristic cyanosis, but instances of late presentation do occur where symptoms appear beyond infancy or early childhood [2]. The late presenters have a higher likelihood of complications such as brain abscesses, stroke, or infections like endocarditis due to prolonged cyanosis and hypoxia [3]. Even after its first description by Niels Stensen in 1672 and description of its detailed pathological features by Fallot in 1888, the first complete anatomic repair was performed by Lillihei only in 1954 in an 11-year-old patient [4–6]. Since then, with the era of early diagnosis and the advent of early primary repair in infancy, in the developed nations, the results of early primary surgical repair have constantly improved significantly with a very low risk of complications. In contrast to these patients, in the developing world, there is a large population of late presenters beyond infancy, childhood, and often adolescence, who have been undiagnosed for many years due to mild or atypical symptoms in early life, inadequate medical surveillance, or geographical barriers limiting access to healthcare. These patients often exhibit more complex anatomical variations, need unique challenges in diagnosis and management, and require extensive surgical procedures, and even after adequate surgical correction, there is a higher risk of postoperative complications [7]. In infancy, although quality of life improves significantly after surgery, late presenters may experience more limitations compared to those who have undergone early repair. The psychological and socioeconomic impact of late-diagnosed TOF cannot be understated, affecting quality of life, employment opportunities, and overall well-being [8]. Some of these issues are detailed in this review. Because details of the socioeconomic features and epidemiological aspects are exhaustive, these aspects are not discussed in detail in this review.

What is late presentation of TOF

Patients with TOF who are categorized as late presenters are those who remain undiagnosed or untreated beyond the age typically recommended for surgical intervention, which has progressively decreased over the years. Historically, the average age for corrective surgery was in the first or second decade of life. However, advancements in diagnostic and surgical techniques have shifted the standard timing of intervention to infancy, often within the first year of life, and currently, surgery around 6 months of age is considered ideal. Late presentation refers to patients who are diagnosed or present for surgery beyond infancy, including those in adolescence and early adulthood. For the purposes of this review, the definition from standard text that classifies any patient over 12 years of age is retained [9]. This group encompasses individuals who may have been minimally symptomatic early in life or those who, despite significant symptoms, have not undergone intervention due to a variety of socioeconomic, geographic, or healthcare accessibility factors.

Late presenters often display variable clinical characteristics. Some patients exhibit minimal cyanosis or symptoms during infancy and early childhood, representing a less severe form of the pathology, with significant right-to-left shunting and cyanosis developing only with advancing age. Others may experience dyspnea on exertion, prompting their initial clinical evaluation. In rare cases, major aortopulmonary collaterals or previously constructed systemic-to-pulmonary artery shunts may maintain acceptable systemic saturation, delaying the need for corrective surgery. However, prolonged cyanosis and hypoxia in these patients predispose them to complications such as cardiac arrhythmias, congestive heart failure, and impaired systolic and diastolic ventricular function due to hypoxic cardiomyopathy and altered hemodynamics. The diagnostic and management strategies for this subgroup are discussed in detail in subsequent sections.

Morphological types and peculiarities

Late presenters with TOF can be divided into five morphological types:

• (i)Classic TOF: This type includes the typical anatomical features with a large VSD, significant pulmonary stenosis leading to obstruction of the RVOT, overriding aorta that straddles the VSD, and RVH. Late-presenting classic TOF may show varying degrees of these features, with some patients presenting with less severe stenosis or different degrees of overriding aorta.
• (ii)Pulmonary atresia with VSD: In this variant, severe pulmonary stenosis progresses to pulmonary atresia, where the pulmonary valve fails to develop or is severely hypoplastic. Blood flow to the lungs is maintained through the patent ductus arteriosus or collateral vessels. Late-presenting cases may have varying degrees of pulmonary atresia, impacting treatment options and prognosis.
• (iii)TOF with absent pulmonary valve: This rare variant involves absent or severely hypoplastic pulmonary valve leaflets, leading to significant pulmonary regurgitation and dilation of the pulmonary arteries. Late presentation can lead to progressive pulmonary artery dilation and right heart dysfunction.

VSD with pulmonary atresia and TOF with absent pulmonary valve form different subsets and are not discussed further.

• (iv)TOF with anomalous coronary arteries: In TOF, coronary artery anomalies are relatively common and have significant implications for surgical management. Approximately 6% of TOF patients exhibit anomalous coronary arteries originating from the opposite sinus of Valsalva or the opposite coronary artery. Notably, 72% of these anomalous vessels cross the RVOT, which is a critical consideration during corrective surgery to prevent inadvertent damage. Additionally, about 6% of patients with TOF have a large conus artery, and 4% present with a coronary arteriovenous fistula. These variations underscore the importance of detailed preoperative coronary artery assessment for proper surgical planning and reduce the risk of complications.
• (v)Complex variants: Late-presenting TOF can also include complex variants such as TOF with additional cardiac defects like atrioventricular canal defects or abnormalities of the systemic venous return.

Late presenters with TOF can exhibit several specific morphological characteristics compared to the classic presentation in infancy or childhood. These variations often reflect the adaptations and changes that occur over time in response to chronic physiological stress and compensatory mechanisms. Here are some peculiar morphological characters that may be observed:

1. RVH: Due to chronic pressure overload from pulmonary stenosis, the right ventricle often becomes hypertrophied. In late-presenting TOF, this hypertrophy may be pronounced and accompanied by myocardial fibrosis, leading to changes in ventricular wall thickness and compliance.

2. Pulmonary artery anomalies: In late-presenting cases of TOF, patients often exhibit either well-developed branch pulmonary arteries or significant major aortopulmonary collateral arteries (MAPCAs). The presence of substantial MAPCAs can provide sufficient pulmonary blood flow, potentially delaying the onset of severe symptoms and, consequently, the timing of medical intervention. This phenomenon is supported by studies indicating that in TOF with pulmonary atresia, approximately 20 to 40% of patients have multiple sources of pulmonary blood flow from the systemic circulation, primarily through MAPCAs.

Additionally, the variability in native pulmonary artery development and the source of pulmonary blood flow in TOF patients underscores the role of MAPCAs in influencing the clinical presentation and timing of diagnosis.

• (iii)Aortic root dilatation and aortic valve regurgitation: Over time, untreated TOF may lead to significant dilation of aortic root and dysfunction of the aortic valve, resulting in regurgitation.
• (iv)Complex VSD: Late-presenting TOF may present with a VSD that is complex in nature, involving multiple defects or unusual locations within the ventricular septum.
• (v)Atrial septal defect (ASD): Coexistence of ASD with TOF is not uncommon, especially in late-presenting patients.
• (vi)Collateral Vessels: In patients with severe pulmonary stenosis or atresia, collateral vessels may develop over time to maintain pulmonary blood flow. These vessels can be extensive and contribute to complex hemodynamics and intraoperative complications.

Natural history

The natural history of late-presenting TOF without treatment is characterized by a variable and often progressive decline in cardiac function and overall health, influenced by the severity of the anatomical defects and the individual’s physiological adaptations (Table 1). Initially, adults with untreated TOF may experience mild symptoms such as occasional cyanosis during exertion, dyspnea on exertion, and fatigue [2, 3]. Over time, these symptoms tend to worsen as pulmonary stenosis progresses or as pulmonary hypertension (extremely uncommon in TOF) develops secondary to chronic hypoxemia. Patients with TOF are at increased risk of infective endocarditis. The presence of RVH and myocardial fibrosis predisposes individuals to arrhythmias such as ventricular ectopy, atrial fibrillation, and sustained ventricular tachycardia. Chronic volume and pressure overload on the right ventricle can lead to right heart failure over time. Symptoms of heart failure, such as peripheral edema, ascites, and hepatic congestion, may become evident as the disease advances. There is increased risk of paradoxical embolism and stroke in the presence of ASD or patent foramen ovale. Pulmonary arterial hypertension might be caused by pulmonary agenesis, hypoplasia and/or thrombosis, or an excessively large systemic to pulmonary collateralls [10]. As symptoms worsen, individuals may experience significant limitations in exercise tolerance, impacting their daily activities and quality of life. Secondary polycythemia exacerbates the blood viscosity and increases the risk of thromboembolic events. Long-term survival without surgical intervention is significantly reduced, particularly as complications such as arrhythmias, heart failure, and infective endocarditis become more frequent and severe. According to the study by Bertranou et al., 66% of patients with TOF not treated surgically live to age 1 year, 49% to age 3 years, and 24% to age 10 years; thereafter, the instantaneous risk of death remains constant [11] (Table 2).

Table 1.

Modes of late death in patients with tetralogy of Fallot

CHF due to hypertension and aortic regurgitation
Sudden death due to atrial flutter, atrial fibrillation
Malignant ventricular arrythmias which are more common in patients with QRS duration of > 180 ms or more than 3 fragmentation of R wave in QRS complex
Higher risk of suicide [12–16]

Table 2.

Problems/higher incidence of complications in repair with advancing age

Residual VSD
Pulmonary incompetence
Restrictive RV physiology leading to CHF
Recurrent pleural effusions
RV/LV dysfunction
Atrial and ventricular arrhythmias, sick sinus syndrome

VSD, ventricular septal defect; RV, right ventricle; LV, left ventricle; CHF, congestive heart failure

Why intervention is still beneficial

Intervention in adult patients with TOF remains highly beneficial, despite the risks associated with late presentation. Surgical repair significantly improves survival, with studies showing a 10-year survival of over 90% in late presenters, compared to only 24% beyond 10 years without intervention. Patients experience marked symptomatic relief, including reduced cyanosis, dyspnea, and fatigue, with most achieving New York Heart Association. (NYHA) class I–II status post-surgery. There is improvement in right ventricle (RV) function. Quality of life is also enhanced through better physical activity levels, improved cognitive function, and increased employment opportunities, along with psychological benefits such as reduced anxiety and depression. Addressing prolonged cyanosis reduces the risk of severe complications like brain abscess, stroke, and endocarditis, while also mitigating long-term risks of arrhythmias and right ventricular failure caused by chronic pressure overload. Early mortality after repair is less than 3% in most experienced centers, with a 30-year survival rate exceeding 85%, enabling many patients to approach a near-normal lifespan with appropriate monitoring and management of residual complications.

However, early and late attrition still occurs due to (a) advanced age at operation, (b) preoperative polycythemia and need for phlebotomy, (c) preoperative RV/left ventricle (LV) systolic/diastolic dysfunction, (d) presence of arrhythmias, (e) high postoperative persistent pRV/LV, and (f) transannular patch (TAP) with free pulmonary regurgitation.

Important considerations in perioperative management

The surgical correction of late-presenting TOF presents several challenges due to the anatomical complexities, physiological adaptations over time, and potential for associated complications (Table 2).

Patients who have minimal cyanosis and minimally impaired systemic organ dysfunction are usually stable patients with no major sequalae. Patients with deep cyanosis with restrictive RV morphology and systemic organ dysfunction are patients with higher surgical risk and require careful management at every step (Table 3).

Table 3.

Complications of surgery in late presenters of TOF and methods to minimize those

Complications	Causes	How to minimise
Arrhythmias	Myocardial fibrosis Altered conduction pathways	Careful selection of anesthetic agents. Monitoring to maintain hemodynamic stability Minimize arrhythmogenic triggers Avoid excessive β adrenergic support, Pacemaker
Bleeding	Coagulopathy due to chronic hypoxia Thrombocytopenia	Folic acid supplements Adequate blood products Hemostatic drugs Preoperative/intraoperative phlebotomy in operating room Minimally invasive approaches where feasible Avoid excessive endotracheal suction, proper hemostasis
Left heart return	MAPCAs Other collateral blood flow	Moderate hypothermia with cooling to 25–26 °C
Transient/persistent myocardial dysfunction	Effects of cardiopulmonary bypass Residual defects Myocardial ischemia Pulmonary regurgitation Tricuspid regurgitation	Minimizing the duration of bypass Avoid injury to coronary arteries Meticulous closure of ventricular septal defect (VSD) Attempt a purely trans right atrial approach or Trans-RV with a minimum ventriculotomy Avoid excessive infundibular resection Avoid liberal use of TAP Preservation of pulmonary valve function (reconstruction/replacement) Preservation tricuspid/pulmonary valve function Prefer milrinone as inotropic agent Need higher filling pressures due to RV diastolic dysfunction Optimize mode of ventilation, duration of ventilation and the degree of positive end expiratory pressure (PEEP)
Pulmonary artery complications	Narrowing Kinking Thrombosis
Infective endocarditis	Prosthetic materials

MAPCA; major aortopulmonary collateral arteries, RV; right ventricle, TAP; transannular patch, VSD; ventricular septal defect, PEEP; positive end expiratory pressure

In addition to more detailed preoperative workup, these patients require correction of anemia or may require phlebotomy to reduce the hematocrit to 60% [17]. Phlebotomy or blood-letting is performed at many centers to ensure a smoother postoperative course and to avoid complications of polycythemia in these patients. Volume replacement is an important consideration to reduce the risks associated with phlebotomy in these patients. Iron deficiency can occur following phlebotomy. To prevent this risk, a minimum volume of blood should be withdrawn to minimize the risk of phlebotomy and at the same time to achieve the objective of a relief in symptoms. This procedure can be performed on an out-patient or in-patient basis. Various techniques have been used. A usual practice of day-care practice is to remove 500 ml blood over 30 to 45 min. While 500 ml is commonly used in adults, individualized approaches may be necessary for smaller patients, those with lower total blood volume, or those at risk of hemodynamic instability. Following this, an equal volume of 0.9% saline or colloid should be administered. Blood pressure should be monitored every 15 min. Relief of symptoms occurs over 12–24 h as systemic blood flow is improved due to reduction of polycythemia. If the symptoms do not improve, phlebotomy may be repeated. Any co-existent iron deficiency should be corrected; the details of diagnosing and managing this are outside the scope of this review.

Major aortopulmonary collaterals can be occluded in the cardiac catheterization laboratory using coils/plugs before surgery. These can also be occluded during intracardiac repair in the operating room. Patients with surgically created systemic-pulmonary shunts need to be secured intraoperatively prior to commencement of cardiopulmonary bypass (CPB). If not addressed preoperatively, MAPCAs can result in a number of complications, including intraoperative systemic hypoperfusion. In spite of preoperative occlusion of MAPCAs, these patients usually have small multiple collaterals due to which there is excessive return of blood in left atrium which may fill up the operative field leading to impaired intraoperative visibility and early myocardial re-warming that impairs myocardial protection and poses a higher risk of postoperative intraparenchymal pulmonary artery bleeding. Many of these collaterals are also around the sternum, making it very vascular, resulting in bleeding and need for re-exploration postoperatively. These patients require efficient cardiotomy suction to cope up with the excessive return, which can lead to damage of blood components and disseminated intravascular coagulation (DIC). It is recommended to have normal/mild/moderate hypothermia with high hematocrit of 35–40% on CPB; cooling to 25–28°C may be needed to reduce the flows and amount of collateral return obscuring visibility and to prevent myocardial warming. Postoperatively, there can be massive hemoptysis, pleural effusion, need for prolonged ventilation, and intensive care unit (ICU) stay. Postoperatively, late-presenting TOF patients may be particularly prone to complications such as flash pulmonary edema due to a sudden increase in pulmonary blood flow to previously under-perfused lungs and hypervolemia in the setting of a small LV. Chronic under-perfusion can lead to pulmonary vascular fragility, while prolonged right ventricular dominance may result in a hypoplastic LV, unable to handle increased pulmonary venous return post-repair. Careful fluid management, preoperative evaluation of LV size, and strategies to gradually increase pulmonary blood flow during surgery are critical to minimizing these risks.

Perioperative use of hemostatic agents and blood products is necessary as these patients tend to have higher risk of postoperative bleeding despite careful hemostasis [18, 19]. In the operating room, it is preferable to avoid nasal intubation as well as unnecessary endotracheal tube suction as there is a higher risk of mucosal bleed. Chronic pressure overload on the RV leads to hypertrophy and fibrosis, affecting ventricular function. Surgical strategies must address right ventricular remodelling and ensure adequate ventricular performance postoperatively. In a prior study, the intraoperative pressure(p)RV/LV measurements were found to be fallacious in determining the adequacy of RVOT resection in patients with TOF, as there is a marked drop in pRV/LV in the early postoperative phase. This phenomenon was presumed to be due to dynamic obstruction caused by spasm of the RVOT, which typically responds to volume expansion and reduction of inotropes, especially those inducing tachycardia. However, in grown-up patients, the likelihood of a fixed obstruction must be carefully considered. Therefore, intraoperative assessment with pressure measurements and transesophageal echocardiography (TEE) becomes mandatory to accurately evaluate the adequacy of RVOT resection and to differentiate dynamic from fixed obstruction [20]. However, this is unpredictable in older patients. As mentioned earlier, there is RVH in these patients with RV dysfunction. Therefore, if possible, right ventriculotomy should be avoided. In case a TAP is necessary, it may be preferable to reconstruct the pulmonary valve or perform pulmonary valve replacement in order to avoid free pulmonary regurgitation (PR).

In addition to multiple small or large collaterals, challenges to surgeons are common due to the presence of anomalies of the pulmonary arteries, including hypoplasia or tortuosity. At the end of the operation, meticulous hemostasis is mandatory. In older patients above 40 years of age, coronary artery imaging to rule out coronary artery disease should be a part of the preoperative evaluation. It is not uncommon to see a dilated aortic root which needs surgical repair or replacement in adult patients with TOF [21, 22]. Late-presenting TOF patients are at increased risk of arrhythmias due to myocardial fibrosis and altered conduction pathways [23]. Arrhythmia management and risk stratification are critical components of perioperative care. It is recommended to avoid excessive β-adrenergic support as the RV is already severely hypertrophied and myocardial oxygen demand is increased. Milrinone is preferred when inotropic support is required. In adults, milrinone-induced hypotension can be difficult to manage in hypovolemic situations, due to less responsive cardiovascular system compared to neonates and infants. In infants, the smaller blood volume allows for quicker stabilization with modest fluid resuscitation, while older patients often require significant volume administration and, in some cases, vasopressor support. Careful volume assessment and titration of milrinone dosage are critical, particularly in the perioperative period.

Early results

Immediate postoperative survival rates are generally lower in late-presenting TOF patients compared to those operated on in infancy, but successful outcomes are still common. In a study by Khan et al., 80 patients (mean age 21 ± 0.21 years) were reported. Early mortality was 8% [24, 25]. Hu et al. studied 219 adults with TOF (mean age, 40 years) who underwent surgical intervention; the 30-day mortality was only 1.4% [26]. In the study by Khajali et al., involving 94 patients with the mean age of 26.7 ± 9.6 years, the in-hospital mortality was 5.3%. Causes of mortality were sepsis with pulmonary valve endocarditis and severe right ventricular failure leading to multi-organ failure [12].

Increased risks of complications such as residual defects, right ventricular dysfunction, and arrhythmias were noted in late-presenting patients with TOF. Khan et al. reported low cardiac output syndrome in 11.25%, pleural effusion requiring tapping in 3.75%, reoperation for bleeding in 3.8%, moderate to severe PR in 25% which occurred in the TAP group only, and atrial arrhythmias in 5% [24]. According to Waqar et al., pleural effusion was seen in 3.9% patients, clinically insignificant small residual VSD was seen in 2.6% patients, moderate to severe PR was seen in 37.1% patients, mild to moderate tricuspid valve regurgitation was seen in 4.8% patients, and moderate RVOT was seen in 5.2% patients [25]. Khajali et al. reported mild and moderate RVOT obstruction in 39.3% and 12.7% of the patients, respectively [12]. In the study cohort of Hu et al., postoperative complications were observed in 30% of patients, with issues such as arrhythmias requiring medical intervention, need for dialysis, hepatic dysfunction, respiratory failure, infections, reoperation, cardiac arrest, use of mechanical circulatory support, and mortality. A multivariate analysis identified several independent risk factors for these complications, including advanced age at the time of surgery, prolonged CPB duration, right ventricular systolic dysfunction, diabetes mellitus, and a history of prior palliative surgery [26].

Late presenters often have longer hospital stays due to the complexity of the surgery and the management of pre-existing conditions. Recovery can be slower, with a higher need for intensive care and longer periods of monitoring. In a series from our institute [13], median inotropic score in postoperative period was 10 (range 5–30) and median duration of mechanical ventilation was 12 h (range 6–48 h). Inotropic score was higher in patients with aortopulmonary collaterals, high preoperative hematocrit, and with right ventricular dysfunction. Patients with a RVOT gradient > 80 mmHg were observed to have a prolonged hospital stay, likely due to increased postoperative right ventricular strain and associated complications. Those who underwent only trans-atrial repair exhibited a lower inotropic score, shorter ICU duration, and overall hospital stay, indicating a more favorable anatomy, possibly consistent with less complex forms such as double outlet right ventricle (DORV) or double-chambered right ventricle (DCRV) [13].

However, compared to patients operated at the ideal age during infancy, these late presenters are at a higher risk of postoperative arrhythmias and residual RVOT obstruction due to long-standing cyanosis and myocardial remodelling. The persistence of high RVOT gradients postoperatively is a recognized indication for reoperation, especially when correlated with symptomatic arrhythmias or progressive RV dysfunction. Studies suggest that addressing residual gradients through re-intervention significantly reduces arrhythmic burden and improves long-term outcomes.

Long-term results

Long-term survival rates for late-presenting TOF patients are lower than those for early-treated patients but are still relatively high. Many patients achieve good functional status. Many late-presenting patients enjoy a reasonably good quality of life, though some limitations in physical activity are more common than in early-treated patients. Nollert et al. reported one of the earliest studies among 104 adults who underwent surgical correction of TOF; actuarial survival rates at 10, 20, 30, and 35 years were recorded at 94%, 93%, 83%, and 72%, respectively, aligning closely with the life expectancy of the general population. The primary cause of mortality was congestive heart failure (n = 3), followed by myocardial infarction (n = 2), and sudden cardiac death (n = 2). It was observed that late mortality increased from 0.24 to 0.94% after 25 years of survival. The causes of late deaths were congestive heart failure (CHF), suicide, and sudden death due to ventricular arrhythmias or sick sinus syndrome [14]. John et al. reported 17 years’ experience of 200 patients > 14 years of age [15]. In the later part of the study, the early mortality was 1.3% with 97% of late survivors leading healthy life and in NYHA class I–II. Rammohan et al. [3] reported their experience of 100 patients > 13 years of age with early mortality of 4% and one late death due to infective endocarditis (IE). 93.6% of patients were in NYHA class I on mid-term follow-up.

Atik et al. reported results of 39 patients with mean age of 26.6 years (15.4% required TAP), in whom actuarial survival rates were 91.2 ± 4.9%, 85.5 ± 7.2%, and 68.4 ± 16.3% at 3, 7, and 15 years, respectively [27] (Tables 4 and 5). A retrospective analysis of 52 patients (28.9 ± 9.9) for TOF by Horer et al. reported eight early deaths (15.4%) and six late deaths (11.5%) of which only 2 were cardiac-related [28]. Analysis of 465 patients (37 ± 14 years) by Egbe et al. reported that 12% of patients experienced either death or required a heart transplant over a follow-up period of 13.6 ± 8.2 years, corresponding to an event rate of 0.9% per year. Identified independent risk factors for mortality included age greater than 42 years, presence of atrial fibrillation, moderate or severe QRS complex (QRS) fragmentation, left ventricular ejection fraction below 50%, right ventricular end-diastolic pressure exceeding 16 mmHg, and left ventricular end-diastolic pressure greater than 16 mmHg [29]. Khajali et al. reported 94 adult patients, who underwent TOF repair; 18% of the cohort underwent a secondary surgical procedure. This secondary surgery encompassed 14 cases of pulmonary valve replacement (PVR) (14.8%) and 3 cases of residual VSD repair (3.1%) [30].

Table 4.

Outcome for late tetralogy of Fallot

Sr no	Author and year of study	Patient population and age at operation (years)	Type of intervention	Early outcomes	Median follow-up	Outcome
01	Khajali Z et al., 2023 [30]	94 adult patients undergoing TOF repair (mean age: 26.7 years)	Total correction; some with prior shunt palliation	In-hospital mortality of 5.3%; significant reduction in tricuspid regurgitation post-surgery	1 year	Tetralogy of Fallot total correction at older age deemed safe with acceptable results; age not a contraindication for TFTC
02	Bhushan R et al., 2022 [31]	45 adult patients undergoing TOF repair (median age: 21 years)	Intracardiac repair using various approaches; Jhajhria Infundibular Resection Adequacy Assessment Technique (JIRAAT)	Right bundle branch block in 14 patients; early postoperative mortality rate of 2%	Not specified	Low mortality; less residual RVOT obstruction; significant improvement in quality of life
03	Lee MG et al., 2021 [32]	293 adult survivors of TOF repair, median age at repair 2.6 years	Trans-atrial repair (51%), right ventriculotomy (34%)	Excellent adult survival (97% overall); arrhythmias in 24% (atrial in 12%, ventricular in 6%); pulmonary valve intervention in 57%	9 years (max 40 years)	Age-adjusted survival: 99% at 20 years, 95% at 40 years, 83% at 60 years. Freedom from PV intervention and arrhythmia decreased significantly by 60 years (16% and 31%, respectively). Excellent functional status in 99.5% (NYHA class I/II)
04	Yasukawa T et al., 2021 [33]	30 adults undergoing surgical PVR for chronic pulmonary regurgitation late after TOF repair (median interval: 29 years)	Pulmonary valve replacement (PVR)	LVSVI remained low; subnormal-SVI group had higher ablation therapy rate pre-PVR; unchanged LVSVI post-PVR	1 year post-PVR (76.7% re-evaluated)	LVSVI did not fully recover after PVR; patients in subnormal-SVI group had elevated BNP levels post-PVR and no difference in clinical event incidence between groups
05	Ducas R A et al., 2021 [34]	230 adults (born 1981–1996) undergoing childhood ToF repair; median follow-up age: 25 years	Annulus-preserving (AP) vs transannular patch (TAP) repair	Reintervention more common in TAP group (72.2% TAP vs 20.2% AP, OR 5.5, P < 0.001); PVR significantly higher in the TAP group	7.9 years (IQR 3.5–12)	Significantly fewer late reinterventions in the AP group; the TAP group had higher PVR needs
06	Egbe AC et al., 2019 [29]	18,353 adult TOF patients with 1230 PVRs performed; median age at PVR: 34 years	Pulmonary valve replacement (PVR) with transcatheter PVR in 7.3%	Temporal increase in admissions for PVR (3.7% early era to 9.6% late era); in-hospital mortality decreased (4.1% early era to 0.8% late era)	Not specified	Proportion of PVR admissions increased; younger age at PVR and decreased in-hospital mortality over time; knowledge gaps about cumulative lifetime risks remain
07	Dłużniewska N et al., 2018 [35]	83 adult patients with repaired TOF (mean age: 30.5 ± 10.7 years)	Long-term follow-up of repaired TOF patients without pulmonary valve replacement	No significant differences in CPET and CMR parameters between groups (< 25 years vs ≥ 25 years post-repair)	Up to 25 years after TOF repair	Good long-term survival and clinical condition; QRS duration correlated with RV function; no significant deterioration in functional status over time
08	Waqar T et al., 2017 [25]	307 patients (mean age: 9.56 ± 4.89 years) undergoing TOF repair after infancy	Primary surgical repair; 4 patients with prior modified Blalock-Taussig shunts	Postoperative complications in 7.8%; pleural effusion (3.9%), complete heart block (0.3%); residual VSD (2.6%); moderate/severe pulmonary regurgitation (37.1%)	30 days	Low 30-day mortality (1.3%); good outcomes in children and young adults undergoing late TOF repair
09	Khan I et al., 2016 [24]	80 adult patients undergoing TOF repair (mean age: 21 ± 0.21 years)	Surgical repair; primary repair and post-palliative procedures	In-hospital mortality: 8%; postoperative complications included low cardiac output syndrome (11.25%), pleural effusion (3.75%), reoperation for bleeding (3.8%), and moderate/severe pulmonary regurgitation in 25% (transannular patch group only)	30 days	Mortality and morbidity rates comparable to international standards. Increasing experience improves outcomes
10	Luijten LW et al., 2015 [36]	453 patients with median age at operation 0.6 years; median age at last follow-up 14.3 years	Transatrial-transpulmonary repair with or without transannular patch (TAP)	Early mortality 1.1%; late mortality 2.4%; overall survival 97.3% at 10 years and 91.8% at 25 years	25 years	TP associated with poorer event-free survival (27.9% TP vs 78.5% non-TP at 25 years); PVR common at longer follow-up
11	Talwar S et al., 2014 [13]	41 adult patients undergoing TOF repair (age range: 30–52 years)	Surgical repair; aortopulmonary collaterals occluded prior to surgery in 28 patients; 24 patients underwent transatrial repair	Early mortality: 2 patients; median duration of ventilation: 12 h (6–48 h); significant correlation between low preoperative oxygen saturation and increased inotropic score, mechanical ventilation, intensive care unit, and hospital stay	42 months	Repair of TOF in and beyond the fourth decade is feasible with acceptable results. Prolonged postoperative course in patients with high hematocrit, low oxygen saturation, right ventricular dysfunction, aortopulmonary collaterals, or high RVOT gradients
12	Atik FA et al., 2004 [27]	39 adults with TOF repair (mean age 26.6 years, range 18–67)	Transatrial/transpulmonary approach (41%), TAP (15.4%)	Hospital mortality 5.1%, late mortality 7.7%; 79.4% survivors in NYHA class I	45.1 months (1–194 months)	Actuarial survival: 91.2% at 3 years, 85.5% at 7 years, 68.4% at 15 years. Late complications include arrhythmias (38.9%), RV dysfunction (38.2%), and moderate/severe PR (26.5%)
13	Nollert G et al., 1997 [14]	71 adult TOF patients undergoing repair (age ≥ 18 years); mean age: 27.7 years	Surgical correction with pulmonary stenosis repair	Operative mortality: 24%; 1-year mortality: 8%; 10-year survival: 94%; 35-year survival: 72%	35 years	Long-term survival was comparable to normal life expectancy. At follow-up, > 80% reported being in NYHA class I or II, with 95% in better condition than before surgery. Repair of TOF in adulthood shows excellent long-term outcomes
14	John S et al., 1986 [15]	200 TOF patients undergoing repair (age > 14 years)	Intracardiac repair; transannular gusset used in 74% of patients in the last 5 years	Hospital mortality: 1.3% in the last 5 years; residual VSD: 1% overall, zero in the last 12 years	17 years	97% of survivors are asymptomatic and leading active lives. Excellent or good hemodynamic results in 88% of recatheterized patients. Repair in adolescents and adults achieves excellent outcomes and easier hemodynamic correction than in children

TOF, tetralogy of Fallot; RVOT, right ventricular outflow tract; TAP, transannular patch; AP, annulus-preserving; PVR, pulmonary valve replacement; LVSVI, left ventricular stroke volume index; CPET, cardiopulmonary exercise testing; CMR, cardiac magnetic resonance; RV, right ventricle; NYHA, New York Heart Association; PR, pulmonary regurgitation; VSD, ventricular septal defect; OR, odds ratio; IQR, interquartile range

Table 5.

Late outcomes for late-presenting tetralogy of Fallot patients undergoing surgical correction

Study	Patient population (age at repair)	Follow-up duration	Key late outcomes
Nollert et al., 1997 [14]	71 adult TOF patients (mean age: 27.7 years)	35 years	10-year survival: 94%, 35-year survival: 72%; late mortality due to arrhythmias, CHF, MI
John et al., 1986 [15]	200 TOF patients (age > 14 years)	17 years	97% survivors in NYHA class I–II; late survival rates similar to age-matched controls
Atik et al., 2004 [27]	39 adults (mean age 26.6 years)	15 years	Actuarial survival 68.4% at 15 years; arrhythmias (38.9%), RV dysfunction (38.2%), moderate/severe PR (26.5%)
Egbe et al., 2019 [29]	18,353 adult TOF patients (median age at PVR: 34 years)	13.6 ± 8.2 years	Mortality 0.9% per year; risk factors: age > 42, AF, QRS fragmentation, LV EF < 50%
Dłużniewska et al., 2018 [35]	83 adults (mean age: 30.5 ± 10.7 years)	25 years	Good long-term survival; QRS duration correlated with RV dysfunction
Ducas et al., 2021 [34]	230 adults with TOF repaired in childhood	7.9 years	Higher PVR rates in TAP patients (65.1%) compared to annulus-preserving (16.3%)
Bokma et al., 2023 [37]	1537 adult TOF patients with repaired TOF	Median 16 years	PVR reduced risk of mortality and VT in RV ESVI > 80 mL/m2 group
Yasukawa et al., 2021 [33]	30 adults undergoing PVR	1-year post-PVR	LV stroke volume index remains low, persistent RV/LV dysfunction in subnormal SVI group

TOF, tetralogy of Fallot; CHF, congestive heart failure; MI, myocardial infarction; NYHA, New York Heart Association; RV, right ventricle; PR, pulmonary regurgitation; PVR, pulmonary valve replacement; AF, atrial fibrillation; LV EF, left ventricular ejection fraction; TAP, transannular patch; ESVI, End-Systolic Volume Index; VT, ventricular tachycardia; SVI, stroke volume index

The risk of developing arrhythmias later in life is significant. This includes both atrial and ventricular arrhythmias. Development of late complete heart block has also been reported. The incidence of severe PR, which may require further surgical or catheter-based interventions, is higher in late-presenting patients. Among 230 adults who underwent repair of TOF as young adults (126 with TAP repair), the median follow-up was 7.9 years (interquartile range (IQR) 3.5–12), re-intervention of any type was significantly more common in the TAP group during both late childhood and adulthood (72.2% TAP vs 20.2% annulus preserving (AP), hazard ratio 5.5, 95% confidence interval (CI) 3.4–9.0; P < 0.001). In the series described by Ducas et al., PVR was almost six times more likely in adults with TAP repair (65.1% TAP vs 16.3% AP, hazard ratio 5.7, 95% CI 3.4–9.7; P < 0.001) [34]. In a retrospective analysis of 284 patients (mean 19.4 ± 2.5 years) with operated TOF by Bisoi et al., 2.1% required reoperation over a mean follow-up period of 4.6 ± 2.3 years [38].

A higher rate of re-interventions is observed in late-presenting TOF patients, often due to progressive RVOT obstruction, PR, or arrhythmias. Bhat et al. reported that pre-existing aortic root dilatation normalizes by 7 years of age in patients with TOF who have been repaired in infancy, whereas it persists into adulthood in the group repaired post-infancy [39]. Coronary artery disease (CAD) requiring revascularization surgery has also been reported after TOF repair [40].

While many late-presenting TOF patients can achieve good functional capacity post-repair, they may still experience limitations in exercise tolerance and physical activity compared to the general population and those who had early repairs. Sadiq et al. demonstrated significant improvement in functional class even with PR. Thirty-five of 36 patients who underwent treadmill testing had good effort tolerance, with an average of 10.47 ± 1.4 metabolic equivalents achieved [41].

However, on long-term follow-up, the late survivors are at risk of complications which may necessitate surgical/catheter intervention if not controlled on medical therapy and form the subject of next discussion.

Pulmonary valve reconstruction

Free PR is well tolerated for a decade or two. However, it results in significant right ventricular dilatation and dysfunction. Varieties of reconstructive procedures have been described in the literature to maintain pulmonary valve competence. However, a perfect everlasting procedure is still elusive. Even the materials to be used in reconstructive procedures differ. Creation of a monocusp, though helpful in the early postoperative recovery of the patient, is prone to progressive deterioration, calcification, and regurgitation [42–44]. It is more so with glutaraldehyde-treated pericardium. Monocusps created out of homografts, autologous pulmonary artery wall, bovine jugular vein, and xenograft conduit meet the same fate. It was considered that polytetrafluoroethylene (PTFE) monocusp is free of deterioration and calcification [45]. However, in follow-up, even PTFE cusp gets calcified (Iyer KS—personal communication).

Temur et al. [46] observed 73.3% freedom from moderate/severe PR in early postoperative period but it was only 40% on mid-term follow-up.

Creation of bileaflet PTFE membrane has shown some promise on mid-term follow-up by Nunn et al. [47]. The reconstructed pulmonary valves were competent in early follow-up with 5–30% regurgitation fraction as judged by cardiovascular magnetic resonance imaging (CMRI) but it remained stable over a follow-up of a maximum 5 years with no stenosis or embolism. Miyazaki et al. [48] created a fan-shaped expanded polytetrafluoroethylene (ePTFE) membrane patch/valve/conduit with bulging sinuses for pulmonary valve reconstruction and have reported promising results. On median follow-up of 5.5 years, there was no valve-related death, peak RVOT gradient was 16.5 ± 13.1 mmHg. There was less than mild PR in 95.9% of the cases during follow-up. Freedom from re-intervention was 92.3% at 5 years and 76.1% at 10 years in small conduits (8–16 mm) and 99.6% and 95.1% at 5 years and 10 years in larger conduits. Overall survival at 5, 10, and 15 years was 96.1%, 95.3%, and 95.3%, respectively.

These findings suggest that routine pulmonary valve reconstruction during primary repair in adults should be limited to cases where pulmonary annulus preservation is feasible and PR reduction is expected to provide long-term benefit. If severe PR is anticipated postoperatively, elective pulmonary valve reconstruction/PVR at the time of primary TOF repair may be preferred over TAP alone, particularly in patients at high risk of RV failure or arrhythmias [34, 37].

Role of PVR

PVR is preferred to correct PR. As in adult age group, a good-sized valve implant is facilitated by an enlarged pulmonary annulus due to chronic PR. Current consensus indications for PVR are enumerated. Compared with repaired TOF patients who did not receive PVR, propensity score–matched individuals receiving PVR have demonstrated a lower risk of death or sustained ventricular tachycardia (VT). This finding was evident in patients with RV End-Systolic Volume Index > 80 mL/m². However, this benefit was not present in patients with RV End-Systolic Volume Index < 80 mL/m² [37].

Although direct comparative studies on primary TOF repair with or without PVR in adults are limited, several retrospective analyses provide valuable insights. Ducas et al. reported that TAP repair was associated with a significantly higher need for late PVR (65.1%) compared to annulus-preserving techniques (16.3%) (odds ratio (OR) 5.7, 95% CI 3.4–9.7; P < 0.001), highlighting the long-term burden of free [34]. Bokma et al. found that elective PVR at the time of TOF repair reduced the risk of VT and mortality in patients with a RV End-Systolic Volume Index (ESVI) > 80 mL/m², suggesting that PVR may provide a protective benefit in high-risk patients [37]. Egbe et al. observed a rising trend in late PVR among TOF patients over time, with an increase from 3.7% in earlier cohorts to 9.6% in later years, reflecting a growing recognition of PVR’s role in optimizing long-term outcomes [29]. These findings suggest that while TAP remains the preferred approach for many cases, primary PVR should be considered in adults at high risk of RV failure or long-term PR-related complications. Further prospective studies are needed to directly compare primary TOF repair with and without immediate PVR in adults, enabling better-informed surgical decision-making.

Operative technique of PVR

PVR should be considered instead of a TAP alone during primary repair in specific clinical scenarios. In cases of severe pulmonary valve hypoplasia or atresia, where the pulmonary annulus is too small to allow adequate blood flow, valve reconstruction or replacement becomes necessary to ensure optimal hemodynamics [34]. Pre-existing right ventricular dysfunction, particularly in adults with long-standing cyanosis, severe RVH, and diastolic dysfunction, increases the risk of postoperative right ventricular failure if free PR is left uncorrected; in such cases, PVR can help preserve right ventricular function and reduce the need for later reintervention [37]. Additionally, significant aortic root dilatation or aortic regurgitation in conjunction with TOF repair may warrant PVR, as it helps mitigate additional volume overload on the LV and prevents progressive cardiac dysfunction [29, 37]. In patients with severe branch pulmonary artery hypoplasia, the presence of unregulated PR can further reduce pulmonary blood flow, worsening hypoxemia and leading to increased postoperative complications. Finally, in individuals with high preoperative hematocrit and polycythemia, uncontrolled PR may exacerbate hemodynamic instability, making PVR a more favorable option to maintain systemic oxygenation and circulatory stability postoperatively [37].

Before embarking on reoperation, it is important to know the relationship of the cardiac structures with the sternum as adhesions are often found between the heart and undersurface of the sternum. Previous operation notes should be reviewed. Functional assessment and volumes of RV and LV competency of aortic and tricuspid valves, sizes of aorta and pulmonary arteries, and size of pulmonary annulus should be measured from preoperative imaging. Site, size, and the status of bilateral femoral and neck vessels should be assessed with Doppler or computed tomography (CT) angiogram in case peripheral cannulation is required. Usually surgical replacement of pulmonary valve is performed through redo-sternotomy or left anterolateral thoracotomy through the 3rd/4th intercostal space. It can be done on CPB with beating heart with precautions to prevent air embolism. These precautions include preoperative evaluation to rule out any interatrial or interventricular communications, Trendelenburg position during arteriotomy, and flooding of the operative field with carbon dioxide. If there is no VSD or ASD or patent foramen ovale (PFO), the surgery can be planned with single arterial and venous cannulae on an empty beating heart with limited dissection of the cardiac structures. If there is an intracardiac shunt or if a concomitant intracardiac procedure is needed, surgery is performed on an arrested heart. In selected patients, minimally invasive replacement of the pulmonary valve can be performed through a second intercostal space with institution of peripheral CPB. When the main pulmonary artery is dilated, it may be closed directly after valve replacement. But usually an anterior patch is required. When the posterior wall is also deficient, the valve is placed in a Dacron or PTFE tube.

Various types of valves are used for PVR. All the tissue valves degenerate and calcify over a period of time though decellularized valves are supposed to last longer. The degeneration is faster in younger patients with TOF due to rapid calcium metabolism. Main advantage of tissue valves is the avoidance of anticoagulation in young patients beyond 3 months. Mechanical valves are preferably avoided in the pulmonary circuit as it is a low-pressure system with anticipated high risk of thrombosis and thromboembolism. However, promising results are now reported in different series with no fear of degeneration and calcification [16, 49].

Herrmann and Brown [50] reported their experience with seven decades of valve implantation for RVOT reconstruction and recommended the following strategy for valve usage: (a) valved bovine jugular vein (Contegra) in young children < 18 years, (b) decellularized pulmonary allografts for adults with pulmonary annulus > 22 mm, (c) non-stented xenografts/stented porcine valves in adults > 18 years of age.

However, in low-middle-income countries, homografts, hand sewn valves, and the Ozaki procedure (fashioning pulmonary valve (PV) with autologous pericardium) are options and have shown promising results [51].

Managing follow-up problems

Residual defects

Masterly inactivity is recommended for small residual VSDs

In isolation, a small VSD with left to right shunt < 2:1 may not need intervention [42]. In some cases, it may be providing a pop-off mechanism, in an extremely rare event of pulmonary arterial hypertension in patients with diminutive peripheral pulmonary arteries [43]. In other situations, an isolated VSD may be closed either in the cardiac catheterization laboratory or surgically.

Residual/progressive pulmonarystenosis

An isolated pulmonary stenosis with no regurgitation may be due to residual valvular stenosis or progressive infundibular hypertrophy/fibrosis [44]. While all forms of significant stenosis (RVOT gradient > 40 mmHg on echocardiography) should be evaluated for intervention, gradients exceeding 80 mmHg are typically considered for surgical correction due to their hemodynamic impact. Pure valvular stenosis, however, can often be managed satisfactorily with percutaneous balloon valvuloplasty, especially in cases where the gradient is predominantly valvular and there is no significant infundibular or RVOT involvement.

Arrhythmias

This subject has been well elucidated by Krieger et al. [23] in a scientific statement from the American Heart Association. Patients are prone to atrial as well as ventricular arrhythmias. Atrial arrhythmias occur in the form of supraventricular tachycardias, multifocal arrhythmias, brady arrhythmias, persistent atrial fibrillation (AF), or atrial flutter (AFL). Reportedly, the high risk factors for atrial arrhythmias include older age at operation, large right atrium(RA)/left atrium (LA) size, hypertension, repeated surgeries, PR, RV scar, increased RV/LV dimensions and volume, and decreased ejection fraction (EF). Persistent AF and AFL are predictors of decreased survival, more so in 4th decade of life. The treatment includes the need of permanent pacemaker implantation (PPI)/chronic resynchronization therapy (CRT), medical therapy, and anticoagulants or catheter-based surgical ablation of aberrant pathways.

Ventricular arrhythmias are the leading cause of sudden death in the adult population. On electrocardiography, QRS duration of > 180 ms and fragmentation of R wave indicate high possibilities of malignant ventricular arrhythmias. Other risk factors include older age at repair, prior systemic to pulmonary shunts, TAP, RV scar, repeated surgeries, CAD, CHF, prior arrhythmias, significant PR and RV/LV dysfunction with increased dimensions and volumes. The treatment includes anti-arrhythmic drugs, correction of surgical defects, automatic implantable cardioverter-defibrillator (AICD) ± CRT and invasive EPS (electrophysiology study) with catheter/surgical ablation. AICDs carry the risk of inappropriate shocks, IE, and lead failure.

Heart transplant

The need of heart transplant is low in these patients. Smith et al. [52] reported only 22 cases of heart transplant in a cohort of 5719 patients with higher mortality in patients requiring heart and lung transplant and with genetic defects. On the other hand, Taguchi et al. [53] have utilized the marginalized post-TOF repaired heart with preserved PV and normal coronaries and ventricular function in very sick recipients with short life span as a bailout procedure. It helps in the increase of donor pool.

Rare late follow-up complications

Occasionally, false or true aneurysm of TAP occurs which needs surgical repair [31]. In such patients, it is important to rule out IE and distal pulmonary arterial tree complications. In TOF, the aortic wall is not normal histologically and may enlarge abnormally in such patients. There may be associated aortic valve regurgitation. These may also need to be addressed surgically. Pulmonary arterioplasty performed earlier may need reintervention again.

Conclusion

Late presentation in TOF encompasses a heterogeneous group of patients who remain untreated or undertreated beyond the first decade of life, including adolescents, adults, and elderly individuals beyond the fourth decade. Each subgroup presents unique anatomical, physiological, and surgical challenges. Operating on TOF in older patients is associated with distinct issues, including long-standing cyanosis, RV hypertrophy, myocardial fibrosis, and complex hemodynamics. Predictors of adverse outcomes include advanced age at surgery, preoperative polycythemia, RV or LV dysfunction, high pulmonary artery pressures, and the presence of arrhythmias.

Surgical correction in late-presenting TOF aims to improve survival, provide symptomatic relief, enhance exercise tolerance, and reduce the risks of long-term complications like arrhythmias, RV failure, and thromboembolic events. Short-term outcomes indicate higher perioperative morbidity and prolonged recovery compared to early-repaired TOF patients, but long-term outcomes demonstrate significant benefits in terms of improved quality of life and functional status. Survival benefit remains substantial, with 10- and 30-year survival rates exceeding 90% and 85%, respectively, in experienced centers.

The choice of surgical strategy also plays a crucial role in determining outcomes. Valve-preserving techniques, when feasible, offer better RV function preservation and reduced risk of re-intervention. In cases requiring transannular patching, valve repair or replacement strategies (e.g., monocusp, bicuspid, or prosthetic valves) are tailored to the patient’s anatomy and expected longevity. Among these, PVR provides durable results in preventing RV dilatation and dysfunction, particularly in older patients.

As surgical techniques and perioperative management continue to evolve, the focus in late-presenting TOF should be on stratifying patients based on age, anatomy, and physiological status to optimize individualized care. Further studies are needed to refine surgical approaches and improve risk stratification, ensuring the best possible outcomes in this complex patient population.

Author contribution

Sachin Talwar: conceptualized the study, contributed to the literature review, writing, drafted the initial and final versions of the manuscript, and coordinated revisions based on peer-review feedback.

Niwin George: contributed to data collection, literature search, writing and critical revision of the manuscript for important intellectual content.

Vishal Vinayak Bhende: assisted in drafting sections related to surgical techniques and perioperative considerations and contributed to formatting tables.

Balram Airan: conceptualizing, provided expert review of the manuscript for accuracy and relevance, oversaw project supervision.

All authors have made substantial contributions to the conception, drafting, and critical revision of the manuscript and approve the final version. Each author meets the International Committee of Medical Journal Editors (ICMJE) criteria for authorship.

Funding

None.

Data availability

Not applicable. However, the cited papers can be shared with editors.

Code availability

Not applicable.

Declarations

Informed consent

Not applicable, as this is a review article.

Consent for publication

All the authors do consent to publication.

Conflict of interest

The authors declare no conflicts of interest.

Ethics committee approval

Not applicable for review article.

Human and animal rights statements

Not applicable.