Hypoplastic Left Heart Syndrome (HLHS)

Hypoplastic left heart syndrome (HLHS) is a congenital heart defect that consists of the underdevelopment, or hypoplasia, of the left side of the heart in various degrees. The most notable feature of HLHS is the reduced size and functionality of the left ventricle (LV). Also, HLHS is associated with stenosis, hypoplasia, or atresia of the vessels or atrioventricular valves on the left side of the heart. A mixture of genetic factors and altered fetal blood flow causes HLHS. Hypoplastic left heart syndrome presents once the ductus arteriosus closes physiologically as tachypnea, cyanosis, heart failure, and cardiogenic shock. Diagnosis can be made pre- or postnatally via echocardiogram. Once detected, surgical treatment is the 1st-line therapy, done in 3 stages.

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Overview

Definition

Hypoplastic left heart syndrome (HLHS) is characterized by the underdevelopment of the left side of the heart. The components of HLHS include:

  • Left ventricle (LV) with moderate hypoplasia, non-functional hypoplasia, or complete atresia
  • Mitral valve (MV) with stenosis or atresia
  • Aortic valve (AoV) with stenosis or atresia
  • Ascending aorta (Ao) with hypoplasia
  • Atrial septal defect (ASD) and patent foramen ovale (PFO)
Hypoplastic left heart syndrome

Hypoplastic left heart syndrome (HLHS) featuring the direction of blood flow (arrows) and the oxygenation of blood:
Red represents oxygenated blood, blue shows deoxygenated blood, and purple shows mixed blood.
RA: right atrium
RV: right ventricle
LA: left atrium
LV: left ventricle
SVC: superior vena cava
IVC: inferior vena cava
MPA: main pulmonary artery
Ao: aorta
PDA: patent ductus arteriosus
TV: tricuspid valve
MV: mitral valve
PV: pulmonary valve
AoV: aortic valve

Image: “Hypoplastic left heart syndrome” by Centers for Disease Control and Prevention. License: CC0, cropped by Lecturio.

Epidemiology

  • Incidence: 2–3 out of every 10,000 live births 
  • Accounts for 2%–3% of all congenital heart diseases
  • Accounts for 25%–40% of neonatal deaths due to cardiac causes 
  • 1.5:1 male-to-female ratio

Variants

There are 3 types of HLHS based on the morphology of the cardiac valves:

  1. Aortic and mitral atresia (interchangeable with HLHS):
    • The most severe form
    • LV is absent or “slit-like” and has no output.
    • Short ascending Ao
    • Dependent on the persistence of a ductus arteriosus for any chance of survival
  2. Aortic atresia plus mitral stenosis:
    • Hypoplastic ascending Ao
    • LV remodeling and hypertrophy related to the degree of stenosis
    • Minimal LV output
  3. Aortic and mitral stenosis:
    • The mildest form
    • Stenosed valves lead to LV hypertrophy and eventual cardiac output failure.

Etiology

  • There is a component of genetic predisposition as noted in the 2.5%–5% recurrence rate in siblings: associated with poorer morbidity (severe neurodevelopmental delay) and higher mortality.
  • Associated with chromosomal anomalies, such as:
    • Turner syndrome
    • Trisomy 13
    • Trisomy 18
    • DiGeorge syndrome
  • Postulated to be secondary to reduced blood flow in utero through stenosed or atretic AoVs, which leads to the underdevelopment of the LV and ascending Ao
  • May also be linked to intrauterine infarction and/or infection

Pathophysiology

Normal cardiac physiology and development

  • Systemic circulation is maintained in utero via the ductus arteriosus and foramen ovale:
    • Fetal body → vena cavae → right atrium (RA) →  foramen ovale → left atrium (LA) → LV → Ao
    • Also, RA → right ventricle (RV) → ductus arteriosus → Ao 
  • At birth, physiologic changes occur:
    • Ductus arteriosus closes → cessation of blood flow from the RV to the Ao → systemic perfusion is reduced
    • Pulmonary arterial pressure decreases → blood begins to flow from the RV to the pulmonary circulation

In HLHS

  • Survival depends on the patency of the ductus arteriosus and foramen ovale or the presence of an ASD to maintain the following circuit:
    • Pulmonary circulation → LA  → ASD/PFO → RA (mixing of oxygenated and deoxygenated blood) → RV → PDA → systemic circulation
    • The blood that is flowing through the Ao has a mix of deoxygenated and oxygenated blood, resulting in hypoxemia.
  • An absence of PDA, PFO, or ASD results in severe cyanosis, acidosis, cardiogenic failure, and shock after delivery. 
  • Progressive, severe hypoxemia and reduced systemic perfusion results in heart failure and end-organ damage.
HLHS vs. normal heart

The components of HLHS vs. a normal heart

Image: “Hypoplastic left heart syndrome” by Mariana Ruiz. License: Public Domain

Clinical Presentation

  • Infants may be symptomatic or asymptomatic at birth depending on the presence and size of an ASD and PDA. Small or intact atrial septa are associated with severe and rapidly progressive symptoms.
  • At birth: pale or gray-tinted skin (“dusky appearance”)
  • 24–48 hours after birth:
    • The physiologic closure of the ductus arteriosus results in the development or aggravation of symptoms.
    • Poor feeding
    • Lethargy
    • Signs of respiratory distress (dyspnea, tachypnea, nasal flaring)
    • Signs of cardiogenic shock (hypotension, weak peripheral pulses, cyanosis, cool extremities, metabolic acidosis, oliguria, or anuria)
  • Physical exam:
    • Single S2 (only the pulmonary valve (PV) can be heard closing)
    • Hyperactive precordium
    • No murmurs are heard.
    • Hepatomegaly 
    • Dysmorphic features of associated chromosomal anomalies

Diagnosis

  • Most cases are detected during a prenatal anatomic scan.
  • Confirmed by an echocardiogram showing:
    • Hypoplastic left heart (hypoplasia of LV, stenotic/atretic mitral and/or AoVs)
    • RV remodeling
    • Increased pulmonary arterial pressure
  • Supportive tests include:
    • Pulse oximetry < 95% 
    • Electrocardiogram (ECG): non-specific
      • Hard to distinguish P waves
      • Signs of RV hypertrophy
    • Chest X-ray: non-specific
      • Cardiomegaly
      • Prominent pulmonary vasculature
  • For patients in cardiogenic shock, blood work and arterial blood gas (ABG) are needed to assess acidosis secondary to lactic acid buildup.
Hypoplastic left heart syndrome - fetal echocardiography

Postnatal transthoracic echocardiography (4-chamber view):
Severe hypoplasia of the LV with hypoplasia of the LA are seen.
LA: left atrium
LV: left ventricle
RA: right atrium
RV: right ventricle

Image: “Hypoplastic left heart syndrome” by Director of Pediatric Echocardiography, Department of Congenital Heart Disease, Evelina Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, UK. License: CC BY 2.0

Management

Emergent management of shock

  • Prostaglandin E1 infusion to keep the ductus arteriosus patent
  • Inotropes for hypotension
  • Bicarbonate infusion for metabolic acidosis
  • Balloon septoplasty to enlarge a small or deficient foramen ovale

Surgical management

  • 3-staged procedure includes the Blalock-Taussig Shunt, Glenn, and Fontan procedures
  • The goal is to create a larger outflow for the LV and pulmonary circulation that bypasses the RV so that it may be used exclusively for systemic circulation.

Prognosis

  • Left untreated, HLHS is fatal within the 1st few weeks of life.
  • Good tolerance to exercise after surgery
  • Children who complete all 3 stages of surgery have a survival rate of 90% into adulthood.

Clinical Relevance

The following genetic syndromes are associated with the development of HLHS:

  • Turner syndrome: a chromosomal aberration that produces a 45-chromosome karyotype with an X0 female phenotype. Presents with decreased sex hormone levels; primary amenorrhea; cardiac, renal, reproductive, skeletal, and lymphatic anomalies; short stature; webbed neck; broad chest; low posterior hairline; and peripheral edema of the hands and feet. 
  • Holt-Oram syndrome: an autosomal dominant condition characterized by the concurrence of congenital cardiopathy, and hypoplastic or aplastic radii and thumbs. 
  • Jacobsen syndrome: a genetic syndrome characterized by the deletion of the long arm of the 11th chromosome. Ventricular septal defect and left heart obstructive malformations, including HLHS, are the most commonly associated cardiopathies in Jacobsen syndrome.

The following conditions are differential diagnoses of HLHS:

  • Atrioventricular septal defect: a rare congenital heart defect characterized by the abnormal development of the atrial and ventricular septa and valves. Infants usually present with cyanosis, dyspnea, pulmonary edema, tachypnea, tachycardia, and eventually develop congestive heart failure.
  • ASD: a common congenital heart defect characterized by the presence of an opening between the 2 atria of the heart. Patients present with dyspnea, increased susceptibility to respiratory infections, cyanosis, and embolism, but the appearance and severity of symptoms will depend on the size of the defect.
  • Ventricular septal defect (VSD): a common congenital heart defect characterized by abnormal communication between the LV and RV that results in the left-to-right shunting of blood flow. Presents as an holosystolic murmur, with progressive signs of heart failure and cardiogenic shock. 
  • MV stenosis: a rare heart defect characterized by the reduced size of the valve communicating the LA and LV. Symptoms vary greatly depending on the size of the valve and whether the malformation is congenital or acquired. Presents as coughing, dyspnea, palpitations, frequent respiratory infections, weakness, and chest pain.

References

  1. Bardo, D. M. E., Frankel, D. G., Applegate, K. E., Murphy, D. J., & Saneto, R. P. (2001). Hypoplastic left heart syndrome. RadioGraphics, 21(3), 705-717. DOI:10.1148/radiographics.21.3.g01ma09705
  2. Kliegman, R. M., M.D., St Geme, Joseph W., MD, Blum, N. J., M.D., Shah, Samir S., M.D., M.S.C.E., Tasker, Robert C., M.B.B.S., M.D., & Wilson, Karen M., M.D., M.P.H. (2020). Cyanotic congenital heart disease: Lesions associated with decreased pulmonary blood flow. In R. M. Kliegman MD, J. W. St Geme MD, N. J. Blum MD, Shah, Samir S., MD, MSCE, Tasker, Robert C., MBBS, MD & Wilson, Karen M., MD, MPH (Eds.), Nelson textbook of pediatrics (pp. 239-2407.e1). https://www.clinicalkey.es/#!/content/3-s2.0-B9780323529501004570
  3. Ohye, R. G., Sleeper, L. A., Mahony, L., Newburger, J. W., Pearson, G. D., Lu, M., . . . Gaynor, J. W. (2010). Comparison of shunt types in the Norwood procedure for single-ventricle lesions. N Engl J Med, 362(21), 1980-1992. DOI:10.1056/NEJMoa0912461
  4. Lara, D. A., Ethen, M. K., Canfield, M. A., Nembhard, W. N., & Morris, S. A. (2017). A population-based analysis of mortality in patients with Turner syndrome and hypoplastic left heart syndrome using the Texas Birth Defects Registry. Congenital heart disease, 12(1), 105–112.
  5. Glauser, T. A., Zackai, E., Weinberg, P., & Clancy, R. (1989). Holt-Oram syndrome associated with the hypoplastic left heart syndrome. Clinical genetics, 36(1), 69–72. DOI:10.1111/j.1399-0004.1989.tb03369.x
  6. Mattina, T., Perrotta, C. S., & Grossfeld, P. (2009). Jacobsen syndrome. Orphanet journal of rare diseases, 4, 9. DOI:10.1186/1750-1172-4-9
  7. Mäkikallio, K., McElhinney, D. B., Levine, J. C., Marx, G. R., Colan, S. D., Marshall, A. C., Lock, J. E., Marcus, E. N., & Tworetzky, W. (2006). Fetal aortic valve stenosis and the evolution of hypoplastic left heart syndrome: patient selection for fetal intervention. Circulation, 113(11), 1401–1405. https://doi.org/10.1161/CIRCULATIONAHA.105.588194

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