Hypoplastic Left Heart Syndrome

Abstract

Hypoplastic left heart syndrome (HLHS) is a complex congenital heart disease (CHD) involving hypoplasia of the left ventricle (LV), aorta (Ao), and mitral valve. HLHS was uniformly fatal in the past, now survivable with 3-stage surgical palliation. However, there is high morbidity and mortality, with 25% of HLHS patients either dying or having a heart transplant within 1 year of age. The causes for such high morbidity and mortality are not well understood, but the majority of deaths are directly or indirectly related to cardiovascular/hemodynamics causes. Studies in a mouse model of HLHS uncover important contributing factors for single-ventricle patients such as the patient’s intrinsic factors related to mitochondrial dysfunction, and derangements in the early stages of embryonic development. The HLHS mutant mice were noted to have metabolic dysfunction accompanied by cell cycle arrest and cardiomyocyte differentiation defects. Intrinsic cell defects may contribute to cardiac failure in the HLHS population. Moreover, strong evidence of the genetic etiology of HLHS has come from the observation that HLHS has a high recurrence risk and is associated with various chromosomal abnormalities. In this chapter, we will review the basic pathophysiology, pertinent pre-and post-operative managements of HLHS and recent advances derived from the HLHS mouse model.

1. Introduction

Hypoplastic left heart syndrome (HLHS) is a complex congenital heart disease (CHD) involving hypoplasia of the left ventricle (LV), aorta (Ao), and mitral valve (MV). While HLHS is relatively rare (prevalence 0.02%) [1], it accounts for 25% of CHD infant deaths [2]. The great surgical advancement in HLHS led to a transition from the only option of comfort care in the 1980s to a three-stage cardiac surgical palliation procedure offering a 50–70% five-year survival [2]. However, about 25% of HLHS patients either died or had a heart transplant within 1 year of their Norwood operation [3]. Most HLHS survivors suffer ongoing morbidity, with a substantial portion of these patients developing heart failure over time, as well as neurodevelopmental delay and neurocognitive impairment that can significantly degrade the health-related quality of life. The causes for such high morbidity and mortality are not well understood, but the majority of deaths are directly or indirectly related to cardiovascular causes [4]. While the causes for the poor cardiac outcomes are multifactorial, our study in a mouse model of HLHS uncovers important contributing factors related to mitochondrial dysfunction [5].

2. The morphologic Spectrum of hypoplastic left heart syndrome

Dr. Maurice Lev first described the hypoplastic left heart as hypoplasia of the aortic tract in 1952 [6]. However, the term HLHS was initially used by Noonan and Nadas in 1958 [7]. HLHS is a diagnosis that incorporates a spectrum of left ventricular inlet, ventricular and outlet obstructions that may include: aortic atresia or stenosis; mitral stenosis, atresia or agenesis (Figure 1); hypoplasia of the ascending aorta that may extend to the entire aortic arch; a non-apex forming left ventricle with variable degrees of left ventricular hypoplasia; commonly, a discrete coarctation of the aorta; and an intact ventricular septum in most patients [6, 7, 8].

Figure 1.

Illustration of 4 types of HLHS and Norwood procedure with modified BTT shunt (e) and Sano shunt (f). AA: aortic atresia, AS: aortic stenosis, BTT: Blalock-Taussig-Thomas shunt, MA: mitral atresia, MS: Mitral stenosis (graphic illustration by Dr. Raymond Morales).

A normal left ventricle has a mitral valve and gives rise to the aorta. Furthermore, the apical portion of a left ventricular septal surface shows finer trabeculations than a morphologic right ventricle, and the subarterial septal surface is smooth (Figure 2a). Hearts with HLHS show variability in the size of the left ventricle (Figure 2b–d), and the types of mitral valve malformations (Figure 3b–e) and aortic valve obstruction (Figure 4b and c) along with the varying degrees of hypoplasia of the ascending aorta and aortic arch (Figure 5a and b) with or without coarctation.

Figure 2.

Variations in the degree of left ventricular hypoplasia in hearts with HLHS. (a) Septal view of a normal left ventricle, (b) hypoplastic left ventricle with a stenotic and dysplastic aortic valve and endocardial fibroelastosis, and (c) three-chamber view showing the muscle bound, non-apex forming hypoplastic left ventricle with endocardial fibroelastosis, mitral valve stenosis and aortic valvar atresia, (d) diminutive and atretic (no inlet or outlet) left ventricular chamber in a heart with aortic and mitral atresia, and the muscle bound left ventricular segment of the heart bulges on the epicardial surface, and the position of the left ventricle is outlined by the anterior and posterior descending coronary arteries.

Figure 3.

Variations in the condition of the mitral valve in hearts with HLHS. (a) Normal mitral valve, (b) normally configured but miniaturized mitral valve with slightly shortened and mildly thickened tension apparatus and mild diffuse endocardial fibroelastosis, (c) stenotic and dysplastic mitral valve in a heart with severe hypoplasia of the left ventricle and prominent endocardial fibroelastosis, (d) floor of the left atrium and an imperforate mitral valve, and (e) completely muscular floor of the left atrium without evidence of a mitral valve in a heart with mitral valve agenesis.

Figure 4.

Aortic valve stenosis and atresia in the setting of HLHS. (a) Normal aortic valve, (b) tricuspid, stenotic and dysplastic aortic valve, and c) aortic valvar membranous atresia, mitral valve stenosis, and thick endocardial fibroelastosis.

Figure 5.

Supracardiac great arteries and the right side of specimens with HLHS. (a) Mildly hypoplastic ascending aorta and large arterial duct, (b) hypoplastic ascending aorta and proximal aortic arch, coarctation of the aorta at the level of a large arterial duct, (c) enlarged right heart with hypertrophy of the right ventricle and an atrial septal defect.

In classical HLHS, the left ventricle has an intact ventricular septum. Ventricular size may vary from a mild degree of hypoplasia to being morphologically absent with no discernible inlet or outlet. The hypoplastic ventricle is commonly muscle bound with a thick myocardial wall causing the hypoplastic left ventricle to bulge on the epicardial surface. The hypoplastic left ventricle almost universally shows endocardial fibroelastosis that, at times, can be quite prominent (Figure 2b–d). Additionally, the left atrium will demonstrate varying degrees of hypoplasia.

A normal mitral valve consists of an anterior and posterior leaflet with tension apparatus attached to papillary muscles (Figure 3a), and the anterior leaflet is in fibrous continuity with the aortic valve. In the setting of HLHS, mitral valve can vary from well-formed but miniature to dysplastic and stenotic to imperforate or congenitally absent (Figure 3b–e).

The normal aortic valve consists of three semilunar cusps (Figure 4a) and the aorta consists of the ascending aorta, aortic arch, isthmus, and descending aorta. Aortic valves in hearts with HLHS can vary from having three cusps to bicuspid and are dysplastic and stenotic or atretic. Hearts with HLHS can have ascending aortas that may uncommonly be mildly hypoplastic (Figure 5a), but most of the time they vary from moderately to extremely hypoplastic with an almost thread-like appearance (Figure 5b). The hypoplastic ascending aorta serves as a conduit to perfuse both coronary arteries in a retrograde manner. In addition, the aortic arch may be hypoplastic. Coarctation of the aorta - a shelf-like, circumferential, paraductal lesion - is common in the setting of HLHS and may be mild to severe. Furthermore, HLHS is ductal-dependent condition, and the arterial duct is usually widely patent and large (Figure 5b). The right heart is enlarged and shows right ventricular hypertrophy. A patent oval fossa or atrial septal defect (Figure 5c) is present. Sometimes, the flap valve of the oval fossa can show aneurysmal dilatation bulging into the right atrium.

Hearts with premature closure of the oval fossa at an early gestational age result in malformations such as mitral atresia or stenosis and/or aortic atresia or stenosis, variable degrees of hypoplasia of the left ventricle, and endocardial fibroelastosis. The severity of the impact on the heart depends on the gestational timing of the closure or restriction of the oval fossa [9]. Figure 6a–c are images of a heart with premature closure of the oval fossa. Rarely, in patients born with premature closure of the oval fossa and inflow obstruction such as mitral atresia and in cases of typical HLHS with inflow obstruction, an escape channel for the pulmonary venous return may be present [10]. This escape channel may be a levoatriocardinal vein that allows pulmonary blood to egress from the left atrium or a pulmonary vein and reaches the right atrium via the left innominate/superior caval veins (Figure 6d) [11]. Rarely the escape of pulmonary venous blood from the left atrium may be accomplished by partial or total anomalous pulmonary venous return [12].

Figure 6.

Right and left heart anatomy of a heart with premature closure of the oval fossa, and a specimen with a levoatriocardinal vein. (a) Septal surface of the right atrium illustrating the prematurely closed oval fossa, (b) dysplastic and stenotic mitral valve, (c) non-apex forming hypoplastic left ventricle with pronounced endocardial fibroelastosis, (d levoatriocardinal vein connecting the left atrium to the left innominate vein.

A hypoplastic left ventricle with aortic stenosis and an intact ventricular septum (Figure 7a) is not classified as an HLHS. Furthermore, isolated cardiac malformations such as a right-dominant unbalanced atrioventricular septal defect (AVSD) (Figure 7b) or a heart with double outlet right ventricle (DORV) with its ventricular septal defect and mitral valve stenosis (Figure 7c and d), both of which have interventricular communications and a hypoplastic left ventricle are arguably not categorized as having HLHS because they do not meet the traditional definition. However, these types of hearts (right-dominant unbalanced AVSD and DORV) have been described as HLHS variants in addition to their hypoplastic left ventricles they had one or more of the expected left-sided obstructive features seen in classical HLHS such as aortic stenosis/atresia or mitral valve atresia/stenosis, hypoplastic aorta or coarctation of the aorta. Hearts with a DORV or a right-dominant AVSD but had only aortic obstruction and a hypoplastic left ventricle that is physiology inadequate should not be classified as HLHS variants just because they require single ventricle surgical palliation such as the Norwood, bidirectional Glenn, and the Fontan procedures. The classifications of these types of hearts continue to be unsettled, and this is a reason the classification of HLHS variants needs to be based not only on morphology but also on genetic studies, and not on the need for single ventricle surgical palliation or describing them as HLHS variants just to make the cardiac malformations easier to understand for the clinician or others not trained in pediatric cardiology. Doing this may skew forthcoming studies concerning DORV, right-dominant unbalanced AVSD, and HLHS [13].

Figure 7.

Specimens with hypoplastic left ventricles that do not meet the criteria of HLHS. (a) Aortic stenosis and intact ventricular septum, (b) right-dominant, unbalanced AVSD, and an atrial septal defect, (c) right ventricle view, DORV and a ventricular septal defect, (d) left ventricular view of C showing the hypoplastic left ventricle, ventricular septal defect, and the stenotic mitral valve.

3. Surgical palliation of HLHS

The surgical palliation of HLHS consists of three, staged procedures: the Norwood, the Glenn, and the Fontan procedures.

The goal of the first two procedures is to prepare the heart for the final Fontan procedure. The ventricular function must be preserved by avoiding a pressure load (avoiding a pressure gradient in the aortic arch) or excessive load (correct-sized shunt), minimizing pulmonary vascular resistance (good-sized atrial communication), maintaining optimal pulmonary artery growth, and preserving the tricuspid valve function by avoiding ventricular dilatation associated with excessive volume work by the ventricle.

The first report of an attempted palliative operation for HLHS was in 1977 by Doty and Knott [14]. All the patients described died of poor right ventricular function or coronary ischemia. Norwood and associates reported the first successful palliative procedure that is still performed today [15].

The crucial components of this procedure can be divided into 3 steps:

1. Anastomosis of the main pulmonary artery with the ascending aorta to provide unobstructed right (systemic) ventricle outflow.

2. Atrial septectomy to allow unobstructed pulmonary venous drainage.

3. Systemic-to-pulmonary shunt as the source of controlled pulmonary blood flow using a Blalock-Taussing Shunt or Sano shunt (right ventricle to pulmonary artery conduit) [16, 17, 18].

The Norwood procedure is performed through median sternotomy; under moderate or deep hypothermia, using circulatory arrest or selective cerebral perfusion; the latter is currently the preferred option. Different materials are used for arch reconstruction; homograft is the most common material used, but there are other options including bovine pericardium, core-matrix, and femoral vein graft.

The systemic-to-pulmonary shunt can be performed by using the modified Blalock-Taussing-Thomas shunt (MBTT) (Figure 1e) or the right ventricle to pulmonary artery shunt (RVPA) which is named the Sano Shunt (Figure 1f).

MBTT shunt is made of polytetrafluoroethylene (PTFE, Gore-Tex): generally 3.5 mm for infants of 2.5–3.5 kg and 4 mm for larger infants.

The 5 mm RVPA shunt is used for neonates between approximately 2.3 and 3.5 kg. If PVR is high, a 6 mm RVPA shunt may be considered.

A randomized clinical trial comparing MBTT and RVPA at 15 North American Centers was performed which includes 275 patients with MBTT and 274 patients with RVPA shunt [16]. Compared with the MBTT group, the patients with RVPA shunt were associated with higher rates of transplantation-free survival at 12 months. By 14 months, the right ventricular end-diastolic volumes were similar in 2 groups [16], however, the RVPA shunt group had more unintended interventions and complications. Data collected over the follow-up period of 32 months showed a nonsignificant difference in transplantation-free survival between the two groups [16].

The second stage procedure is the bidirectional Glenn procedure that consists of a Cavo-pulmonary anastomosis which is usually is performed between 3 and 6 months of age. Viegas et al. reviewed 14 years of experience on 36 patients younger than 90-day-old and reported no mortality, but 90% of patients required Glenn patch augmentation. The indications to perform a Glenn procedure within the first 90 days of life are persistent hypoxemia, signs of ventricular dysfunction, and atrioventricular valve regurgitation [19].

Finally, the third stage procedure is total cavopulmonary connection or the modified Fontan procedure. There are two different surgical techniques for this procedure, namely, the lateral tunnel with intra-atrial PTFE graft and the extracardiac PTFE conduit; these procedures were popularized in an attempt to avoid late supraventricular arrhythmias [20]. The expandable Gore-Tex graft (Peca-labs) allows for dilatation of the Fontan conduit in the cardiac catheterization suite [21].

In 2002, Akintuerk et al. from Giessen, Germany were the first to describe the hybrid approach to HLHS, which is a combination of surgical intervention (application of bilateral branch pulmonary artery bands) and catheter intervention (placement of ductal stent) as primary palliation for neonates with HLHS [22]. In the United States, Galantowicz and Cheatham reported the results of this procedure in 2005 [23].

The results of the Norwood procedure have improved over the last few decades to where it is unethical not to offer this procedure to all newborns with HLHS; cardiac transplant is considered if there is any contraindication for the Norwood operation or Hybrid procedure.

4. Pre and post-operative care of HLHS

Adequate pre-operative management of HLHS requires knowledge of the fetal circulation in this disorder. In patients with aortic atresia and very severe aortic stenosis—in general, there is a lower pO2 to the fetal brain with probably decreased blood flow to the brain as well. There is retrograde flow into coronaries in these instances and the ascending aorta is quite small. Normally the lungs will receive only 11% of the combined ventricular output [24], but the blood flow that the lungs see in HLHS fetus is usually higher [25]. In HLHS, it is conceivable that the relatively higher oxygen saturation could impact the normal microvascular development in the pulmonary artery and veins [26].

Postnatally, pulmonary venous return (normally fully saturated blood) must be routed to the right atrium. This mixes with desaturated blood in the right atrium and is ejected by the right ventricle. By default, the right ventricle supplies both systemic (through the PDA) and pulmonic circulations. Blood may need to flow retrograde to supply head and neck vessels and coronaries arteries. The delicate balance between systemic vascular resistance and pulmonic vascular resistance plays a major role. As suggested in the above section, ischemia of the brain and coronaries may occur.

In the postnatal period, we need an adequate interatrial communication, widely patent ductus arteriosus and a balanced pulmonary vascular resistance (PVR) to systemic vascular resistance (SVR). There is an inherent tendency for high pulmonary blood flow—in otherwise uncomplicated cases, with concurrent systemic steal. The right ventricle is volume overloaded at baseline. So, the immediate goals of pre-op care rest on preserving ductal patency and balancing PVR and SVR. One needs to be able to diagnose a high pulmonary to systemic flow ratio (Qp:Qs) state. Some of the clinical manifestations include hypotension, decreased urine output, delayed capillary refill, and lactic acidosis. Patients may also present with tachypnea, increased work of breathing, and respiratory distress.

4.1 Keeping the duct patent

The ductus arteriosus can be kept patent via the use of prostaglandin E₁ (PGE₁). The previously described starting dose range of 0.05–0.10 mcg/kg/min [27] has fallen out of favor to a lower starting dose of 0.01 mcg/kg/min [28]. It is most probable that these previously higher doses were the starting doses for patients who had not been prenatally diagnosed; and who came to medical attention later in the neonatal period. The risk of precipitating apnea is higher at higher starting doses. The recommended maintenance dose of PGE is 0.01–0.04 mcg/kg/min. At our institution, we will use doses as low as 0.003 mcg/kg/min–0.005 mcg/kg/min while patients await surgical repair. There are still institutions that will maintain their patients on PGE₁ for prolonged periods of time.

The other means by which the ductus arteriosus can be maintained patent is through stenting of the ductus arteriosus. For patients with HLHS, this is generally done as part of the Hybrid procedure.

4.2 Limiting pulmonary blood flow

Pulmonary blood flow may be limited by manipulating pulmonary vascular resistance. This may be done by the use of sub-ambient oxygen otherwise called hypoxemic mixture [29]. The literature on this is sparse; particularly there are no randomized controlled trials. There has been hesitation to use this widely due to concerns about the cellular effect of hypoxemic mixture on tissue oxygenation. The other concern is that a non-intubated patient receiving a hypoxic mixture may hypo-ventilate or become apneic due to prostaglandin administration; therefore, the PaO2 levels may fall drastically [30]. The use of a hypoxemic mixture requires vigilance in terms of frequent checking of blood gases—to look at PaO2 and base deficit. Attempts to maintain Qp:Qs of approximately 1:1, with an ideal goal for PaO2 of 35–45 mmHg should be made. A useful thing to be aware of is that a central line placed in the right atrium of a patient with HLHS and aortic atresia is generally representative of an arterial gas in such patients. Hypoxemic mixture can be administered via high flow nasal cannula or via oxy-hood or a combination of both or through the endotracheal tube of an intubated patient.

Adjusting the ventilator settings of an intubated patient to allow for higher PaCO2 will also restrict pulmonary blood flow, as well as blending CO₂ into the circuit [31, 32]. The latter is also not commonly practiced.

4.3 Optimization of systemic circulation

One can increase systemic circulation by use of afterload reduction agents such as milrinone—which can be titrated to effect as we monitor saturations; clinical cardiac output, base deficit, lactate levels, and PaO2 [2]. Optimization of oxygen-carrying capacity by keeping hematocrit >40% is also ideal. Ultimately, if all these maneuvers fail and one still needs to wait for intervention, then muscle relaxation of the patient may need to be considered in order to decrease metabolic demand, fully take over respiratory support and manipulated PaCO2.

Some of the maneuvers to limit pulmonary blood flow and increase systemic circulation are listed in the table below.

Limiting pulmonary blood flow	Augmenting systemic blood flow
Hypoxemic mixture	Good intravascular volume
PaCO2	Increasing oxygen-carrying capacity
Intubation and mechanical ventilation	Milrinone (afterload reduction)
Muscle relaxation	Muscle relaxation

4.4 Special considerations

Neonates with a restrictive atrial septum are usually quite ill-appearing with hypoxia and heart failure. The keys to management prior to cardiac catheterization intervention are intubation; ventilation; maintaining good blood volume; inotropic support in the form of a dopamine infusion or epinephrine infusion and continuing prostaglandin. It should be noted that increasing the PGE may worsen the clinical picture as there may be a transient increase in the blood return to the left atrium with no egress. Administration of sodium bicarbonate to mitigate the acidotic milieu and alerting the cardiac catheterization team as well as the surgical team are crucial. The atrial level communication in a patient with HLHS is superior in position and often times the tissue is very thick. As such, the cardiac catheterization intervention to establish atrial level patency can be challenging. If a balloon atrial septostomy cannot be effectively performed, then static ballooning may be done (alternatively stent implantation across the restrictive PFO) and if that fails, the surgical opening of the atrial septum is indicated. Blalock-Hanlon procedure (described in 1948 by Alfred Blalock and C. Rollins Hanlon) [33] is not usually performed for HLHS patients.

Infants with moderate-to-severe tricuspid valve insufficiency and/or poor right ventricular function from the very beginning pose an especially high degree of challenge for the cardiac intensive care physician. Some considerations in their management include ventilation; institution of diuretics; inotropic support; heart failure/cardiac transplant evaluation and supportive care/palliation team care involvement.

The patient with HLHS and severe pulmonary venous obstruction will develop marked hypoxemia over time. This hypoxemia may progress after a period of apparent well-being. The goal for these patients until surgical intervention—is to intubate, provide hyper-ventilation, increase FiO2, and increase SVR using inotropic support. A severe degree of pulmonary venous obstruction is a surgical emergency and may require rescue via extracorporeal membrane oxygenation (ECMO).

4.5 Non-cardiac pre-op management

Genetic evaluation should include chromosome microarray and whole-exome sequencing, if indicated. A screening renal and head ultrasound is also recommended. Feeding the patient with HLHS pre-operatively is also important. Those with relatively balanced circulations—should feed by mouth. For those in whom we may be concerned about their systemic circulation—total parenteral nutrition may be the judicious approach to avoid complications such as necrotizing enterocolitis [2].

4.6 Post-operative management of the HLHS

The post-operative management of the HLHS patient is dependent on which initial procedure is undertaken. In general, there are three first-stage palliation procedures—Norwood procedure with MBTT shunt; Norwood procedure with Sano shunt; and the Hybrid procedure as mentioned in the above section.

The initial management of patients with Norwood MBTT shunt revolves again around achieving that fine balance between pulmonary and systemic flows. If the shunt is relatively large, the patient may have too much pulmonary blood flow and all the maneuvers to limit those as described in the prior section may be instituted. If the shunt placed is long or narrow and relatively resistive and or patient has high pulmonary artery pressure or PVR, then one may find oneself in the situation where there is a need to increase the SVR (use of epinephrine, norepinephrine, vasopressin, calcium) to drive flow through the shunt; to administer volume; and, in extreme cases, to Administrator pulmonary vasodilators in the form of inhaled nitric oxide. These maneuvers are intended to be temporary as the infant’s circulation adapts. The management of these patients post-operatively requires great skill and expertise. One also needs to ensure patency of the shunt by administering anticoagulation—usually in the form of heparin drip—which could later be transitioned to Enoxaparin or Aspirin or both. The regimen of anticoagulation is institution-dependent.

The patients who undergo the Norwood procedure and Sano modification are, in general, less cerebrally challenging to care for. Their cardiac output is highly dependent on pre-load and single ventricular function and less so on a potentially tenuous balance between Qp and Qs. Volume administration and inotropic support generally are sufficient.

Both procedures require judicious monitoring and aggressive treatment of dysrhythmias.

4.7 Hybrid procedure

The Hybrid procedure involves placement of a PDA stent and bilateral PA bands and, if needed, atrial septostomy [22, 23]. The management of patients post-operatively after a Hybrid procedure can be very similar to the way we manage patients post a Norwood procedure and MBTT shunt. Balancing Qp:Qs is important. Keen attention should be paid to the maintenance of duct patency with anticoagulation and/or anti-platelet therapies.

Patients should be observed closely for signs of stent migration either into the pulmonary artery or the aorta as well as for the possibility of PA band migration. Retrograde arch obstruction from the migration of the stent can be screened through daily 4-limb blood pressure measurements. Intermittent echocardiographic assessment can assist in early diagnosis.

4.8 Second stage palliation

The Glenn procedure is the second stage in the HLHS palliation. By far, it is much less challenging to manage these patients post-operatively. The expectation is that these patients will exit the operating room extubated. If the patient had a reassuring pre-Glenn catheterization study, then the hope is that this would have translated into a successful procedure.

In terms of the respiratory system, post-operative care lies in the avoidance of high positive end-expiratory pressure (PEEP) and high PVR states. Through avoidance of hyperventilation, one may manipulate PaCO2 to optimize flow in the Glenn circulation should the patient be intubated. Augment cardiac inotropy, if necessary. Oftentimes, a combination of milrinone and epinephrine drips post-operatively works well. Pain control and, later, effective diuresis are also important. Cerebral congestion from the new passive circulation to the pulmonary arteries can be a source of significant patient discomfort. Simple maneuvers such as elevating the head of the bed can contribute to great patient comfort by using gravity to promote anterograde blood flow from the cerebral to the pulmonary circulation.

Monitoring these patients for desaturation relative to their physiology is also important; and assessing for the common causes of a desaturated Glenn patient is crucial. The desaturated Glenn patient may pose a serious dilemma for the ICU team. The use of 100% FiO₂ and inhaled nitric oxide can be employed. Ultimately, the patient may need to be intubated. In such instances, cardiac catheterization procedure should be pursued to investigate the possible causes. Ensuring adequate hemoglobin levels for Glenn’s physiology is important. If the patient requires additional pulmonary blood flow, then an aortopulmonary shunt may be added to the system [34].

These patients require monitoring for high chest tube output and pleural effusions/chylothorax.

4.9 Third stage

The third stage of palliation is called the Fontan procedure or total cavo-pulmonary anastomosis. Similar to the Glenn procedure, acute post-operative management includes avoidance of high PEEP, and high PVR triggers. The majority of Fontan patients will return from the operating room extubated. Typically, the saturations in a patient post Fontan procedure will be around 92–95%—barring the presence of collaterals or pulmonary vein desaturations. They are preload dependent—at some institutions, the initial post-operative fluid management involves giving patient one and half times maintenance fluid volume. After the first 24–36 h, effective diuresis is then initiated.

Inotropic support may involve the use of epinephrine, milrinone, and/or dopamine. Most recently, the potential beneficial use of vasopressin post-operatively has been explored [35].

Arrhythmias are not infrequent. Postoperatively Fontan patients should be observed for supraventricular tachyarrhythmias of all forms (atrial tachyarrhythmias, re-entry tachyarrhythmias, and junctional arrhythmias).

Like in the Glenn patients, the post-operative Fontan patients require monitoring for high chest tube output and pleural effusions/chylothorax.

Any evidence of an acutely failing Fontan physiology [36, 37] should be anticipated and acted upon expeditiously. If there is evidence of an acutely failed Fontan physiology—serious consideration should be given to taking down the Fontan circuit [38].

5. Possible etiologies for HLHS

5.1 Reduced blood flow—“no flow, no growth” is a possible etiology of hypoplastic left heart syndrome

Reduced blood flow through the left side of the developing heart is the most prevalent hypothesis in the causation of HLHS. Abnormal blood flow has a negative effect on the shear forces applied to the developing heart which in turn impacts the growth of the left ventricle. Any experimental manipulation to decrease left ventricular preload during embryonic development by either obstructing the left atrioventricular canal flow [39], inserting a balloon in the left atrium [25], or by placing an occluder in the foramen ovale [40] resulted in cardiac phenotypes of HLHS in chick embryos and fetal lambs. This hypothesis is further supported by the observation of the HLHS phenotypes in human fetuses with foramen ovale restriction [41] and premature closure of foramen ovale (Figure 6).

5.2 Fetal aortic valve stenosis and HLHS

A group of fetuses with aortic valve stenosis with dilated or normal-sized left ventricles in mid-gestation were found to develop into HLHS [42, 43]. In this group of patients, the aortic stenosis in the developing heart resulted in left ventricular dysfunction, myocardial damage, and decreased left ventricular flow which led to HLHS after birth [43, 44]. However, after successful aortic valvuloplasty for aortic stenosis in human fetus, some patients did not have an improvement in their left ventricle growth and ended up with single ventricle palliation [42]. Therefore, intrinsic defects of left ventricular cardiomyocytes cannot be excluded.

6. Complex genetics in HLHS

Strong evidence of the genetic etiology of HLHS came from the observation that HLHS has a high recurrence risk [45] and is associated with various chromosomal abnormalities [46, 47]. Identifying the genetic causes of HLHS may yield deeper insights into the molecular mechanism driving the pathogenesis of HLHS. In families with HLHS, often bicuspid aortic valve (BAV) is also observed, indicating a genetic link between these two congenital heart lesions [48]. Paradoxically, BAV is the most common CHD (prevalence 1–2%) and is clinically important because of the morbidity and mortality of associated phenotypes, specifically aortic valve disease and aortic aneurysm/dissection (aortopathy). Indeed, BAV underlies aortic valve disease in >50% of patients of all ages undergoing valve surgery [49]. The recurrence of left-sided congenital heart defects in first-degree relatives of a proband of HLHS is about 10–15%, suggestive of a strong but heterogeneous genetic component [45, 47, 50, 51, 52]. In addition, there are approximately 30% of fetuses with HLHS that have extracardiac abnormalities [53]. Analysis from the Society of Thoracic Surgeons database from 2002 to 2006 demonstrated mortality after Norwood procedure was significantly worse in HLHS neonates with non-cardiac abnormalities and/or syndromes with higher unfavorable results in patients with chromosomal defects [54].

6.1 Possible genetic etiologies associated with HLHS

1. Syndromes with HLHS as a cardiac phenotype: Holt-Oram syndrome caused by TBX 5 mutations [55], Rubinstein Taybi syndrome caused by CREB binding protein mutation [56, 57], Smith-Lemli-Opitz syndrome [58], and Noonan syndrome [59, 60].

2. Chromosomal abnormalities: chromosomal abnormalities were noted in 10% of HLHS including trisomy 13 [61, 62], trisomy 18 [62, 63], trisomy 21 [62, 64], Turner syndrome [62, 65], and DiGeorge syndrome [62, 64]. Turner syndrome with HLHS is associated with significant mortality [54, 66].

3. Copy number variants: Jacobsen syndrome (11q24-qter deletion) [67], Alagille syndrome (20p12.2-p12.3 deletion) [68], dup 1q21.1, dup 16p13.11, dup 15q11.2-13, dup 22q11.2, and del 2q23.1 [69], del14q23.3 [70]. Copy number variants were reported to be associated with more than 10% of single ventricle lesions including HLHS [71, 72, 73]. However, copy number variants of undetermined significance in neonates with HLHS are not associated with worse clinical outcomes [73].

4. Gene mutations: Notch1 [72, 74, 75], Nkx2.5 [72, 75, 76], HAND1 [72, 75, 77], GJA1 [78], Lrp2 [79], SMAD3 [80], ERBB4 [81], PROX1 [82]. Pathological mutations in cardiomyopathy-associated genes-MYBPC3, RYR2 and MYH6 were noted in HLHS patients with cardiomyopathy which suggests a shared clinical and genetic pathway between HLHS and cardiomyopathy [83].

6.2 Cell intrinsic defects in the pathogenesis of HLHS

The complex genetics of HLHS is further supported by analysis of HLHS mutant mice through the usage of a large-forward genetic screen [5]. Lo et al. recovered 8 HLHS mutant lines with exome sequencing demonstrating no shared mutations among the 8 HLHS lines [5, 84] (Figure 8). The results indicate that HLHS is genetically heterogeneous with a multi-genetic etiology. Through extensive analysis of one HLHS mutant line, Ohia identified defects in mitochondrial bioenergetics, nitric oxide (NO) metabolism, and cell cycle regulation [5]. The Ohia HLHS mouse model exhibits mid-to-late gestation lethality with heart failure characterized by severe pericardial effusion with poor cardiac contractility. This is associated with decreased cardiomyocyte proliferation and increased apoptosis [5]. Ultrastructural analysis showed the myocardium with poorly organized thin myofilaments and altered mitochondrial morphology [5]. Dynamic changes in mitochondria morphology play an important role in the developmentally regulated metabolic switch from glycolysis to oxidative phosphorylation, a process that also plays a critical role in regulating cardiomyocyte differentiation [85]. This entails closure of the mitochondrial permeability transition pore (mPTP) and formation of a mitochondrial transmembrane potential (ΔΨ_m) mediating oxidative phosphorylation. Using primary cardiomyocyte explants from the E14.5 Ohia HLHS mouse heart, Lo et al. measured the ΔΨ_m, in cardiomyocytes from the right (RV) and left ventricle (LV). A reduction was observed in both the RV and LV cardiomyocytes. To determine whether the abnormal open state of the mPTP is a cell-autonomous defect, mouse induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) were used to verify the cardiomyocyte and mitochondrial defects. Those studies indicate that the mitochondrial dysfunction, and proliferation and differentiation defects observed in the Ohia HLHS heart tissue are cell autonomous. Hence, the feasibility to model HLHS-HF in iPSC-CM is suggested by studies of the mouse model of HLHS [5]. Furthermore, modeling using human iPSC-CM showed early heart failure (HF) patient iPSC-CM have increased apoptosis, redox stress, and failed antioxidant response. This was associated with mitochondrial permeability transition pore (mPTP) opening, mitochondrial hyper-fusion, and respiration defects. In contrast, iPSC-CM from patients without early-HF had a hyper-elevated antioxidant response with increased mitochondrial fission and mitophagy. Single-cell transcriptomics also showed dichotomization by HF outcome with mitochondrial dysfunction and endoplasmic reticulum (ER) stress associated with early-HF. Importantly, oxidative stress and apoptosis associated with early-HF were rescued by sildenafil inhibition of mPTP opening or TUDCA suppression of ER stress. Together, these findings support a new paradigm for modeling clinical outcomes in iPSC-CM, demonstrating that uncompensated mitochondrial oxidative stress underlies early-HF in HLHS [86].

Figure 8.

Ohia HLHS phenotypes. (A, F) newborn (P0) or E16.5 hearts from wild-type (A) and HLHS mutants (F). Hypoplastic aorta and LV are visible in the HLHS mutant. (B, G)) Histopathology showing the cardiac anatomy of HLHS mutant (G) and littermate control (B) at birth (P0) and E14.5. Compared with controls, the HLHS mutant exhibited hypoplastic aorta and aortic valve atresia, hypertrophied LV with no lumen, and MV stenosis, arrowhead. (C–E, H–J) Ultrasound color-flow imaging of normal fetus (C–E), showing robust flow from the aorta (Ao) and pulmonary artery (PA). In the HLHS mutant (H–J), the aorta showed only a narrow flow stream, whereas the pulmonary artery showed robust flow. 2D imaging revealed hypoplastic LV (H), as compared with the normal-sized LV in the control (C) (modified with permission from reference 5).

6.3 Increased mitochondrial oxygen consumption is associated with poor cardiac outcomes in HLHS patients

Oxygen consumption rate (OCR) from peripheral blood mononuclear cells in 16 biventricular-CHD (BV-CHD) patients, 20 single ventricle-CHD (SV-CHD) patients, and 22 healthy controls without CHD demonstrated higher respiratory maximum and reserve in single ventricle patients with poor cardiac outcome (death or cardiac death) [87]. Apart from that, we observed a lower OCR in HLHS patients with cardiac dysfunction compared with normal controls [87]. Of the 8 SV-CHD patients with Fontan completion, we observed significantly higher OCR in 4 patients with poor cardiac outcomes (death or cardiac death) (Figure 9a and b). These changes were observed in two related respiratory parameters—respiratory maximum and respiratory reserve. In contrast, SV-CHD patients with normal cardiac function showed significantly lower OCR when compared to either SV-CHD patients with HF, BV-CHD patients, or healthy controls (Figure 9a and b). Given SV-CHD with systemic RV are known to have worse clinical outcomes than SV-CHD patients with systemic LV [88, 89, 90], we reanalyzed the data focusing on only SV patients with HLHS (systemic RV), either with or without HF. This analysis yielded similar findings with significantly higher respiratory maximum and reserve observed in the post-Fontan HLHS patients with HF. However, we observed a lower OCR in HLHS patients without HF (Figure 9c and d). In addition, there is no difference between post-Fontan SV or HLHS patients either with or without HF when compared to BV-CHD patients or control subjects in basal glycolysis by measurement ECAR. Heart tissue from Ohia mutant mice with HLHS showed elevated basal respiration (Figure 9e and f). This is also associated with HF, shown by in utero echocardiography observation of poor cardiac contractility, low cardiac output, and severe pericardial effusion in the Ohia HLHS fetal mice [5]. In contrast, genetically identical Ohia mutants without CHD showed reduced basal respiration but entirely normal cardiac function (Figure 9g and h). Together these findings suggest intrinsic metabolic defects in patients with HLHS with a shared genetic etiology with their structural heart defects. These results are supported by studies demonstrating that mitochondrial metabolism [91] plays an important role in heart development and the regulation of cardiomyocyte differentiation [85]. These findings suggest systemic defects impact mitochondrial respiration in SV-CHD patients.

Figure 9.

Mitochondrial respiration in SV-CHD patients and Ohia HLHS mutant mouse heart. (a, b) Mitochondrial respiration in the PBMCs of SV-CHD patients ≥10 years old with and without HF vs. age-matched controls (a) and BV-CHD patients (b). (c, d) Mitochondrial respiration in the PBMCs of HLHS-CHD patients ≥10 years old with and without HF vs. age-matched controls (c) and BV-CHD patients (d). (e–h) Basal OCR in LV and RV heart tissue from E14.5-16.5 Ohia line with Sap130/Pcdha9 mutations known to cause HLHS. This analysis was obtained using the Seahorse Analyzer. (e, f) Data was obtained from litters comprising wild-type (WT) (n = 7) and HLHS (n = 4). (g, h) Quantitively analysis of 5 Sap130/Pcdha9 mutants with normal cardiac anatomy without HLHS (e, f) and six WT controls. (a–d) Mean ± SEM with one-way ANOVA test. Subjects’ numbers are indicated in the legend for the graphs. (e–h) Bar graphs show mean ± SEM with Student’s t-test. Each dot represents one mouse embryo’s heart tissue (modified with permission from reference [81]).

6.4 The complex genetics driving the cardiac and neurodevelopmental outcomes in HLHS patients

Many studies have shown patients with complex CHD, especially those with HLHS, have impaired neurodevelopment associated with developmental delay, learning disabilities, behavioral deficits, and cognitive impairment [92, 93, 94, 95, 96, 97]. The etiology of the cognitive impairment in HLHS had been generally assumed to arise from hypoxic injury (prior to palliation) and/or complications from medical/surgical management. Clinical studies analyzing various risk elements (cardiopulmonary bypass time, hypothermia, etc) in the Single Ventricle Reconstruction Trial showed such factors can explain some of variance in HLHS outcomes which suggests patient intrinsic factors may contribute to the cause of the poor neurodevelopmental outcomes in SV-CHD patients [92]. A shared genetic etiology for CHD and brain abnormalities has been indicated by a large-scale human genomic study [98] as well as studies of HLHS mutant mouse models. Mouse models of HLHS were also observed to exhibit brain abnormalities, suggesting that mutations causing the cardiac lesion in HLHS can also cause brain defects that could contribute to the poor neurodevelopmental outcome in HLHS patients [99, 100, 101]. The brain phenotypes observed in the HLHS mice included microcephaly, which has also been reported in HLHS patients [99, 101]. Also seen were other brain abnormalities largely confined to forebrain structures, including the cerebral cortex, hippocampus, corpus callosum, cerebellum, and olfactory bulbs. In contrast, the midbrain and hindbrain structures were mostly spared. These findings suggest abnormal brain development with regional brain dysplasia may drive the neurodevelopmental delay and neurocognitive impairment associated with HLHS.

7. Summary and conclusion

A diagnosis of HLHS was once uniformly lethal, but now survivable with multi-stage surgical palliation. However, it is still associated with significant morbidity and mortality. Through clinical research and animal models, our understanding of the pathophysiology and underlying mechanisms is actively evolving to improve outcomes for this vulnerable population of patients.

Acknowledgments

We thank Miss Olivia Phillips for her computer assistance in preparing the figures.

Disclosure

The contributing authors declare no competing interests in this article.