Version May 2024
INTRODUCTION — Hypoplastic left heart syndrome (HLHS) is characterized by a diminutive left ventricle (LV) and small left-sided structures incapable of supporting the systemic circulation (figure 1). If left untreated, HLHS is universally fatal. Surgical and medical interventions have improved outcomes, but mortality and morbidity remain high.
The anatomy, physiology, clinical features, and diagnosis of HLHS will be reviewed here. Management and outcome of HLHS and management of patients following the Fontan procedure are discussed separately. (See "Hypoplastic left heart syndrome: Management and outcome" and "Management of complications in patients with Fontan circulation".)
PREVALENCE — HLHS is the most common form of functional single-ventricle heart disease, with a birth prevalence of approximately two to three cases per 10,000 live births in the United States [1-4]. HLHS accounts for 2 to 3 percent of all congenital heart disease [1,2]. A male predominance (male to female ratio approximately 1.5:1) is observed in most population-based and clinical studies [4,5]. The reported overall incidence is likely underestimated because of the indeterminate rate of spontaneous abortions and elective termination of pregnancy of affected fetuses.
Despite its low incidence relative to other congenital cardiac disorders, HLHS, if left untreated, is responsible for 25 to 40 percent of all neonatal cardiac deaths.
ANATOMY — HLHS is a spectrum of cardiac malformations with normally related great arteries characterized by underdevelopment of the left heart with significant hypoplasia of the left ventricle (LV) including atresia, stenosis or hypoplasia of the mitral and/or aortic valves, and hypoplasia of the ascending aorta and arch [6]. The anatomic variants of the disease are often distinguished by the status of the mitral and aortic valves (figure 1):
●Mitral atresia and aortic atresia (MA-AA) subtype – The MA-AA subtype is the most extreme form of HLHS. Both valves are atretic, and there is either an absent or a slit-like LV cavity and diminutive ascending aorta. With no possibility of LV output, this anatomic subtype is unequivocally identified as HLHS.
●Mitral stenosis and aortic atresia (MS-AA) subtype – In the MS-AA subtype, the ascending aorta is severely hypoplastic and systemic output is ductal-dependent. Depending on the degree of mitral stenosis, LV pressures may be subsystemic, systemic, or even suprastemic. The degree of ventricular hypertrophy is also variable, but there is usually severe LV systolic dysfunction.
●Mitral stenosis and aortic stenosis (MS-AS) subtype – At the mildest end of the spectrum is the "borderline left heart" (the MS-AS subtype), in which both valves are stenotic but not atretic. In some patients with MS-AS, the mitral and aortic valves are near-normal in size but a combination of LV diastolic and systolic dysfunction, or valvar stenosis, results in inadequate LV systemic output.
Neonates with HLHS physiology require a patent ductus arteriosus (PDA) to maintain adequate systemic circulation. Indeed, a ductal-dependent systemic circulation is a defining characteristic of the syndrome.
PATHOGENESIS — The pathogenesis of HLHS is thought to be multifactorial, with alterations in blood flow and genetic factors contributing to the development. However, underlying causal mechanisms are poorly understood. Other possible contributing factors that have been suggested include intrauterine infarction, infection, and a selective left ventricular (LV) cardiomyopathy.
Altered blood flow — One prevalent theory hypothesizes that "primary" anatomic defects of isolated left heart structures lead to altered blood flow through the left side of the heart, resulting in secondary malformations of the LV and outflow tract structures (sometimes called the "no flow, no grow" theory). The flow-based theory is supported by observational studies of human fetuses that reveal that aortic valve stenosis is an isolated early finding among fetuses who develop progressive prenatal hypoplasia of the left heart and neonatal HLHS [7]. In addition, animal studies have shown that obstructing flow results in severe structural heart defects [8,9].
Genetics — There is growing evidence that genetic factors play a key role in the development of HLHS [10]. HLHS can occur in association with chromosomal aneuploidy and microdeletion syndromes, including Turner syndrome, Jacobsen syndrome, trisomy 13, trisomy 18, and DiGeorge syndrome [11-13]. However, these represent the minority of cases of HLHS and most affected neonates are nonsyndromic.
Single-gene mutations (eg, NKX2-5) have also been implicated [14]. In one study, putative pathologic copy number variants were noted in 14 percent of patients with single-ventricle heart defects, compared with 4 percent of control subjects [15]. The genetic role in HLHS is also supported by the finding that the recurrence risk for HLHS in subsequent siblings is approximately 8 percent [16].
Genetic syndromes and genetic variants appear to be associated with greater risk of mortality and poor neurocognitive outcome in patients with HLHS [15,17,18]. (See "Hypoplastic left heart syndrome: Management and outcome", section on 'Outcome'.)
PHYSIOLOGY — With hypoplastic or atretic mitral and aortic valves, and a diminutive left ventricle (LV), the right ventricle (RV) must support both the pulmonary and systemic circulations. Survival is dependent on a patent ductus arteriosus (PDA) to ensure adequate systemic perfusion (from the RV to the aorta) and a nonrestrictive atrial septal defect (ASD) to ensure adequate mixing of oxygenated and deoxygenated blood. The relative distribution of RV output to the systemic and pulmonary circulations is dependent on the relative resistances of these parallel circuits.
At birth, there is typically a short "honeymoon" period when the ductus arteriosus is unrestrictive and pulmonary arteriolar resistance is relatively high. As a result, there is no restriction of adequately oxygenated systemic blood flow from the RV across the PDA and into the aorta. During this period, infants may be relatively asymptomatic. However, two normal physiologic post-delivery events, PDA closure and a reduction in pulmonary vascular resistance, lead to a decrease in systemic perfusion and an increase in pulmonary blood flow. If HLHS is not recognized and treated (eg, with prostaglandin E1 infusion) prior to the occurrence of these physiologic events, cardiogenic shock and respiratory failure will ensue. (See "Physiologic transition from intrauterine to extrauterine life", section on 'Circulatory changes'.)
In an estimated 10 percent of cases of HLHS, there is an inadequate or no defect in the atrial septum to allow egress of pulmonary venous return from the left atrium back to the RV [19-21]. A restrictive or intact atrial septum can result in increased pulmonary venous congestion and inadequate interatrial mixing of oxygenated and deoxygenated blood. Patients with this physiology present after delivery with severe cyanosis and acidosis and rapidly deteriorate with hemodynamic instability and shock. This occurs most commonly in patients with mitral atresia. Urgent intervention to create a larger atrial communication is required for survival [21]. In some patients with restrictive or intact atrial septum, the left atrium may be partially decompressed if there is a levoatrial cardinal vein, but this often does not preclude the need for eventual ASD enlargement. (See 'Postnatal presentation' below and "Hypoplastic left heart syndrome: Management and outcome", section on 'Initial stabilization'.)
CLINICAL FEATURES
Postnatal presentation — In most cases, HLHS can be identified on prenatal ultrasonography and fetal echocardiography. (See 'Prenatal diagnosis' below and "Congenital heart disease: Prenatal screening, diagnosis, and management".)
In neonates who present postnatally, the timing of presentation varies and is dependent on the size and presence of an atrial septal defect (ASD) and patency of the ductus arteriosus. (See 'Physiology' above.)
●Infants who do not have a restrictive ASD (approximately 90 percent of infants with HLHS) typically have a "honeymoon" period immediately after birth because of adequate systemic perfusion through a patent ductus arteriosus (PDA) and initially relatively high pulmonary vascular resistance. In some cases, a dusky appearance due to cyanosis is noted in the newborn nursery, but other patients may appear normal and are occasionally discharged home [22]. As the PDA begins to close and pulmonary vascular resistance decreases, infants become symptomatic with a decrease in systemic perfusion manifested by diminished peripheral pulses and increasing pulmonary blood flow, which eventually leads to hypotension, acidosis, tachypnea, and respiratory distress. Symptoms can rapidly progress from cyanosis, increased respiratory distress, and poor feeding to heart failure and cardiogenic shock. (See 'Physiology' above and "Neonatal shock: Etiology, clinical manifestations, and evaluation".)
●Infants with a restrictive or intact atrial septum present shortly after delivery with severe cyanosis and respiratory distress because of inadequate interatrial mixing of oxygenated and deoxygenated blood and increasing pulmonary venous congestion [19-21]. Without the urgent creation of an adequate interatrial communication, patients will develop cardiogenic shock and die.
If left untreated, 95 percent of neonates with HLHS die within the first few weeks of life [23].
Infants with HLHS are more likely to be born prematurely or at low birth weight than infants without HLHS [24]. Fetuses with HLHS have decreased growth velocity in late pregnancy compared with unaffected fetuses, resulting in small for gestational age presentation [25].
Physical examination — The following clinical features are typically found in the natural course of HLHS, although timing varies depending on the size of the ASD and patency of the ductus arteriosus:
●Cyanosis – Cyanosis is the most common feature of HLHS. The degree of cyanosis is determined by the relative states of pulmonary and systemic blood flow (ie, infants with very high pulmonary flow rates may have very mild degrees of cyanosis). Cyanosis does not resolve with supplemental oxygen.
●Tachypnea – Occasionally, if the ductus arteriosus remains patent and the pulmonary vascular resistance drops, tachypnea and respiratory distress can be part of the early presentation as pulmonary blood flow increases. Symptoms may also include retractions or gasping.
●Heart sounds – Typically, no murmur is heard during cardiac auscultation. The second heart sound is single and loud, reflecting the absence of the aortic valve component and the associated pulmonary hypertension. In some infants, a pulmonary flow murmur may be present and the systolic murmur of tricuspid regurgitation may also be auscultated.
●Cool extremities – There may also be diminished peripheral pulses in infants with a low systemic output state.
●Hepatomegaly – Hepatomegaly may develop in patients with right ventricular (RV) dysfunction or tricuspid regurgitation.
●Dysmorphic features – Patients should also be examined for dysmorphic features suggestive of an underlying syndrome. (See 'Genetics' above.)
DIAGNOSIS — Echocardiographic imaging, whether pre- or postnatal, is sufficient in most cases to make a diagnosis of HLHS. In both fetal and postnatal examinations, the anatomic features including a diminutive left ventricle (LV), abnormal mitral and aortic valves, and a hypoplastic ascending aorta are easily identified and confirm the diagnosis of HLHS.
Prenatal diagnosis — The diagnosis of HLHS is made prenatally in approximately 50 to 75 percent of cases [19,26,27]. Prenatal diagnosis can be made on routine obstetrical ultrasound screening in the second trimester of pregnancy (typically between 18 and 24 weeks gestation), if the clinician recognizes the constellation of anatomic findings for HLHS (diminutive LV, abnormal mitral and aortic valves, and a hypoplastic ascending aorta). Some fetuses during this gestation timeframe may have a normal-sized LV without obvious flow disturbance across the mitral and aortic valves. Therefore, careful attention to other more subtle features can help identify those patients at risk for evolving HLHS. These may include [7]:
●Left-to-right flow at the level of the atrial septum (normally, right-to-left in utero)
●Monophasic mitral valve inflow
●Retrograde flow in the transverse arch (due to the ascending aortic and coronary arterial flow being supplied via the ductus arteriosus)
●LV systolic dysfunction
Antenatal diagnosis can also be made with fetal echocardiography, which may be performed due to family history or other fetal anomalies [26]. (See "Congenital heart disease: Prenatal screening, diagnosis, and management".)
Prenatal diagnosis allows time for parental education and counseling, for planning delivery at a tertiary care center with expertise in caring for neonates with HLHS [28], or for termination of pregnancy. Earlier screening (ie, during the first trimester) can identify some fetuses with HLHS and may also detect other noncardiac abnormalities [29]. In one report, first trimester screening was associated with a higher rate of pregnancy termination compared with second trimester screening [29].
Based on the available case series, there does not appear to be a difference in mortality between live-born infants diagnosed prenatally compared with postnatally diagnosed patients [26,27,30]. In a retrospective multicenter cohort of 591 infants with single-ventricle anatomy (HLHS in 66 percent), infants diagnosed prenatally were less likely to have acidosis, renal insufficiency, and shock at the time of stage I palliation compared with infants diagnosed postnatally. They also had shorter duration of mechanical ventilation postoperatively following stage I, but other postoperative outcomes, interstage course, and outcomes after stage II palliation (bidirectional Glenn) were similar between groups.
Postnatal diagnosis
Echocardiography — The characteristic echocardiographic findings of HLHS are a diminutive LV, abnormal mitral and aortic valves, and hypoplastic ascending aorta, which confirm the diagnosis (movie 1). Segmental anatomy is normal, and the ventricular septum is intact. The mitral and/or aortic valves may be atretic or stenotic. The ascending aorta is often small and can be extremely diminutive in cases with aortic atresia. Ductal flow is typically bidirectional (right-to-left in systole). An atrial septal defect (ASD) is essential for survival, and flow is left to right.
Other studies — Although not diagnostic of HLHS, pulse oximetry, chest radiography, and electrocardiography (ECG) are often performed in the initial evaluation.
●Pulse oximetry – Due to right-to-left flow across the patent ductus arteriosus (PDA) and mixing of oxygenated and deoxygenated blood, most neonates with HLHS will have an abnormal postductal saturation on pulse oximetry. For neonates not diagnosed prenatally, pulse oximetry screening may be more sensitive for detecting HLHS than physical examination alone [31]. (See "Newborn screening for critical congenital heart disease using pulse oximetry".)
●ECG – Right-axis deviation and right ventricular (RV) hypertrophy are common ECG findings in patients with HLHS; however, these are nonspecific findings and are difficult to distinguish from the typical RV predominance seen in the ECG of normal neonates [32].
●Chest radiography – The chest radiographic findings vary and are nonspecific. In infants with increased pulmonary blood flow, typical findings include cardiomegaly and increased pulmonary vasculature. In infants with a restrictive or intact atrial septum, the chest radiography will reveal a "white out" appearance similar to that seen with obstructed total anomalous pulmonary venous connection.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis for a newborn presenting with cyanosis, respiratory distress, and poor perfusion includes (see "Approach to cyanosis in the newborn"):
●Other cyanotic congenital heart defects (table 1) (see "Identifying newborns with critical congenital heart disease" and "Diagnosis and initial management of cyanotic heart disease in the newborn")
●Noncardiac causes of respiratory distress and cyanosis (eg, sepsis, pneumonia, persistent pulmonary hypertension of the newborn) (see "Overview of neonatal respiratory distress and disorders of transition" and "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates" and "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis")
Echocardiography distinguishes HLHS from these other conditions. (See 'Echocardiography' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Congenital heart disease in infants and children".)
SUMMARY AND RECOMMENDATIONS
●Anatomy – Hypoplastic left heart syndrome (HLHS) is characterized by underdevelopment of the left-sided heart structures with significant hypoplasia of the left ventricle (LV), stenosis or atresia of the mitral and/or aortic valves, and hypoplasia of the ascending aorta and aortic arch (figure 1). (See 'Anatomy' above.)
●Prevalence – The prevalence of HLHS is approximately 2 to 3 cases per 10,000 live births. Although HLHS accounts for only 2 to 3 percent of all congenital heart disease, it is a major congenital cardiac cause of neonatal mortality. (See 'Prevalence' above.)
●Pathogenesis and physiology – The causes of HLHS are unknown and are likely multifactorial. One proposed mechanism is that abnormal fetal development of left-sided heart structures (ie, the mitral and/or aortic valve) result in altered flow and consequent hypoplasia (sometimes called the "no flow, no grow" theory). Genetic factors also play a key role. The result of the anatomic defects in HLHS is that the right ventricle (RV) supports both the pulmonary and systemic circulation. Survival is dependent on a patent ductus arteriosus (PDA) for systemic perfusion and an unrestrictive atrial septal defect (ASD) for sufficient mixing of oxygenated and deoxygenated blood. (See 'Prevalence' above and 'Pathogenesis' above and 'Physiology' above.)
●Presentation – The timing and severity of presentation vary in neonates who are not diagnosed prenatally and are dependent on the presence and size of an ASD and patency of the ductus arteriosus. (See 'Postnatal presentation' above.)
•Neonates who do not have a restrictive ASD appear to be asymptomatic during a "honeymoon" period after delivery and become symptomatic with PDA closure and as the pulmonary vascular resistance falls.
•Neonates with a restrictive or intact atrial septum are symptomatic at birth as there is inadequate interatrial mixing of oxygenated and deoxygenated blood and increasing pulmonary venous congestion due to limited egress of blood from the left atrium.
●Physical findings – Physical findings that are commonly observed in the natural course of HLHS include cyanosis, respiratory distress, cool extremities, and decreased peripheral pulses. Typically, no murmur is heard during cardiac auscultation. (See 'Physical examination' above.)
●Diagnosis – The diagnosis of HLHS is made by echocardiography (movie 1). Antenatal diagnosis is possible during a routine obstetrical ultrasound screening in the second trimester of pregnancy. (See 'Diagnosis' above and "Congenital heart disease: Prenatal screening, diagnosis, and management".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Audrey Marshall, MD, who contributed to an earlier version of this topic review.
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