Cyanotic congenital heart defects

Cyanotic heart defects (CHDs) are congenital cardiac malformations that commonly affect the atrial walls, e.g., the right atrium (RA) or left atrium (LA); ventricular walls, e.g., the left ventricle (LV) or right ventricle (RV); heart valves; or large blood vessels. Common causes include genetic defects (e.g., DiGeorge syndrome), maternal conditions (e.g., diabetes), and spontaneous genetic mutations. Pathophysiologically, cyanotic heart defects are characterized by a right-to-left cardiac shunt, which leads to deoxygenated blood entering the systemic circulation. The resulting hypoxemia manifests clinically as cyanosis, which may occur as acute, life-threatening episodes. Other symptoms include failure to thrive, characteristic heart murmurs, and symptoms of heart failure. Diagnosis is confirmed through visualization of the defect on echocardiography. Further diagnostic findings include low oxygen saturation and characteristic x-ray findings. Heart defects requiring treatment are repaired via catheter procedures or surgery. Supportive medical therapy is required in patients with heart failure (e.g., diuretics, inotropic agents) or if surgery cannot be performed (e.g., prostaglandin). If untreated, most cyanotic heart defects are fatal within the first year of life.

Commonly associated conditions and risk factors of cyanotic congenital heart defects

General pathophysiological processes

• CHDs result from the disruption of the normal cardiac morphogenesis sequence.
• CHDs may lead to the formation of connections between the right and left heart (i.e., shunts).
• In cyanotic CHDs: right-to-left cardiac shunting → blood flow from the right to the left heart → deoxygenated blood entering the systemic circulation → cyanosis

General clinical features

• “Blue babies”: pale gray or blue skin color caused by cyanosis
• Feeding problems and failure to thrive
• Exertional dyspnea, tachypnea, and fatigue
• Hypoxemia ^[1][2]
• Symptoms of heart failure (see “Acyanotic congenital heart defects”)
• Nail clubbing may occur later in life.

In approximately 50% of infants with CHDs, a routine newborn physical examination reveals no abnormalities. A normal physical examination does not rule out CHD. ^[3][4]

General treatment considerations ^[5]

• Ductal-dependent CHDs: a group of CHDs that require the patent ductus arteriosus (PDA), which supplies either pulmonary or systemic circulation, to sustain life until surgery can be performed ^[6]
  • PDA supplies systemic circulation in the following:
    • Transposition of the great arteries
    • Hypoplastic left heart syndrome
    • Coarctation of the aorta
    • Critical aortic valve stenosis
  • PDA supplies pulmonary circulation in the following:
    • Tricuspid atresia
    • Critical pulmonary valve stenosis, tetralogy of Fallot
  • Treatment: administration of prostaglandin E1 infusion
    • Example: IV alprostadil infusion (off-label) ^[7][8]
    • Mechanism of action: prevents the ductus arteriosus from closing, creating an intentional shunt to allow mixing of deoxygenated with oxygenated blood
    • Monitor respiratory status and hemodynamic parameters. ^[7]
• In patients with heart failure ^[9]
  • Decrease fluid volume and lower pulmonary vascular resistance with diuretics or ACE inhibitors.
  • Improve the contractility of the heart with inotropic agents (e.g., digoxin).
• Antibiotic prophylaxis for bacterial endocarditis during dental procedures ^[10][11]
  • For all patients with unrepaired cyanotic CHDs
  • During the first six months after surgery
• Surgical repair is required in most cases.

Urgently consult critical care and pediatric cardiology for any neonate or infant presenting with cyanosis or shock. ^[7]

The “5 Ts” of cyanotic CHDs: Tetralogy of Fallot, Transposition of the great vessels, Tricuspid valve anomalies, Total anomalous pulmonary venous return, and persistent Truncus arteriosus

Overview ^[12]

• Definition: tetralogy of Fallot (TOF) is the simultaneous occurrence of the following four defects:
  • Right ventricular outflow tract obstruction (RVOTO) due to pulmonary infundibular stenosis
  • Right ventricular hypertrophy (RVH)
  • Ventricular septal defect (VSD)
  • Overriding aorta (the aorta is displaced above the VSD)
• Other cardiac defects associated with TOF ^[13]
  • Atrial septal defect (ASD)
  • PDA
  • Anomalous coronary arteries ^[14]

RVOTO: Right ventricular hypertrophy, Ventricular septal defect, Overriding aorta are the characteristics of Tetralogy of FallOt.

Epidemiology

• Prevalence: 4–5/10,000 live births in the US ^[15]
• The most common cyanotic CHD ^[16]

Etiology

• Typically sporadic ^[17]
• Associated with the following genetic disorders:
  • DiGeorge syndrome ^[18][19]
  • Down syndrome ^[20][21]
• Maternal exposures during pregnancy
  • Alcohol consumption
  • Phenylketonuria ^[22][23]
  • Diabetes ^[24][25]

Pathophysiology

• During fetal development, anterior and superior deviation of the infundibular septum → misaligned VSD with overriding aortic root and subsequent RVOTO
• Physiologic blood flow is determined by the severity of RVOTO.
  • A large VSD → equal pressures in the right and left ventricles → blood flow along the path of least resistance
  • Severe RVOTO → flow from RV to LV → desaturated blood entering the circulation via the aorta

Clinical findings

• Infants with mild TOF may be asymptomatic on initial examination.
• Mild to severe cyanosis, which depends on the severity of the RVOTO
  • Mild obstruction → more pronounced left-to-right shunt via VSD → little or mild cyanosis
  • Severe obstruction → more pronounced right-to-left shunt via VSD → severe cyanosis
• Tet spells: intermittent hypercyanotic, hypoxic episodes with a peak incidence at 2–4 months after birth ; ^[26][27]
  • Associated with psychological and physical stress (e.g., crying, feeding, defecation)
  • Caused by either an increase in pulmonary vascular resistance (PVR) or a decrease in systemic vascular resistance (SVR) → intermittent worsening of RVOTO and ↑ right-to-left shunting ^[28][29]
  • Spells occur suddenly and are potentially lethal.
• Untreated children tend to squat: squatting → ↑ SVR → ↓ right-to-left shunt → ↑ blood flow to pulmonary circulation → ↓ hypoxemia → relief of symptoms
• Cardiac examination findings
  • Harsh systolic ejection murmur at the left upper sternal border
  • Single S2
  • Possible RV heave and systolic thrill
• CHF symptoms (see “Overview” in “Heart failure”)

In patients with TOF, the auscultated murmur is determined by the amount of blood flow across the RVOTO. Therefore, during tet spells, the murmur may disappear.

Diagnostics

• Prenatal diagnosis: Most cases are now diagnosed before birth due to improvements in fetal echocardiography. ^[30]
• Imaging
  • Echocardiography (confirmatory test)
    • Detection of the main features of TOF
    • Quantification of right ventricular outflow tract pressure gradient
    • Supplementary cardiac catheterization may be performed.
  • Chest x-ray
    • Boot-shaped heart (due to upturned cardiac apex and RVH)
    • Normal or decreased pulmonary vascular markings
    • Concave pulmonary artery segment
• ECG
  • Right axis deviation
  • Prominent anterior R waves (V1–V2)
  • Prominent posterior S waves
  • Right atrial enlargement and RVH (P pulmonale)
• Pulse oximetry: ↓ SpO₂
• Hyperoxia test: helps to distinguish cardiac from pulmonary causes of cyanosis

Treatment ^[5][31]

• Severe RVOTO: PGE1 infusion until surgery ^[8]
• Acute hypoxia (tet spells) ; ^{[7] [32]}
  • Initial interventions
    • Administer oxygen; (e.g., 100% FiO₂ via NRB).
    • Knee to chest position, squatting
    • IM morphine (off-label) ^[7]
  • Subsequent interventions: Consider if no improvement.
    • IV sodium bicarbonate (off-label): to correct metabolic acidosis ^[7]
    • IV fluid resuscitation
    • Vasopressors, e.g., phenylephrine (off-label) ^[7]
    • IV beta blockers, e.g., propranolol (off label) ^[7]
• Heart failure
  • Inotropic agents (e.g., digoxin) and loop diuretics (e.g., furosemide)
  • ACE inhibitors are not recommended in patients with TOF because they may decrease SVR and promote tet spells.
• Surgical repair: performed within the first year of life ; ^[33][34]
  • VSD repair: patch closure of the ventricular septal defect ensuring correct aortal positioning above the left ventricle
  • Enlargement of the RVOTO: resection of the obstructive infundibular musculature
  • If early surgical management is not possible: palliative shunts ; ^{[35] [36]}
    • Blalock–Thomas–Taussig shunt: a palliative surgical procedure for TOF that connects the subclavian artery to the pulmonary artery with an interposed graft
    • Central shunt
    • Others (e.g., Potts shunt, Cooley shunt, Waterston shunt, Sano shunt)
• Follow-up care: to prevent long-term complications, such as heart failure, arrhythmias (e.g., ventricular tachycardia), and neurodevelopmental impairment

Prognosis

• Without surgery, ∼ 50% of patients do not live past the first three years of life. ^[37]
• With corrective surgery, over 90% of patients live to > 25 years of age. ^[38]

Overview

• Definition: anatomical reversal of the aorta and the pulmonary artery
• Other cardiac defects associated with TGV
  • VSD ^[39]
  • Left ventricular outlet obstruction ^[40]
  • Abnormal valves and/or coronary arteries

Epidemiology

• Prevalence: 2–4/10,000 live births in the US ^[15][16]
• Accounts for ∼ 20% of all cyanotic CHD cases ^[16]

Etiology

• Often multifactorial or unknown
• Intrauterine risk factors: infants born to mothers with diabetes ^[5][24]
• Genetic syndromes: seen in ∼ 1% of patients with DiGeorge syndrome ^[41]

Pathophysiology ^[42]

• Failed spiraling of the aorticopulmonary septum → RV emptying into the aorta and LV into the pulmonary artery → complete isolation of the pulmonary and systemic circuits → ↓ oxygenated blood entering the systemic circulation
• Fatal, unless mixing occurs via an intracardiac shunt (e.g., PFO, VSD, ASD) or via an extracardiac connection (e.g., PDA)

Clinical findings

• Postnatal cyanosis (not affected by exertion or supplemental oxygen)
• Tachypnea
• Cardiac examination findings
  • Single, loud S2
  • There is often no murmur.
  • Diminished femoral pulses
• If concurrent VSD is present: systolic murmur at the left sternal border

Diagnostics ^[5]

• Prenatal diagnosis: TGV is difficult to diagnose with fetal ultrasound. ^[43]
• Imaging
  • Echocardiography (confirmatory test)
    • Pulmonary artery arising from the left ventricle
    • Aorta arising from the right ventricle
  • Chest x-ray
    • “Egg on a string” appearance of the heart
      • The enlarged, globular heart resembles an egg lying on its side.
      • The string represents the superior mediastinum that appears narrow due to stress-induced thymic atrophy.
    • ↑ Pulmonary vascular markings
  • MRI (rarely done) showing the aorta arising from the right ventricle and the pulmonary trunk originating from the left ventricle
• ECG: often normal
• Pulse oximetry: ↓ SpO₂

Treatment ^[44]

• Initial postnatal management: Initiate mixing between the two parallel circulations to ensure adequate systemic oxygenation.
  • Infusion of PGE1 to prevent closure of the PDA ^[45]
  • Balloon atrial septostomy ^[46][47]
    • Objective: to enhance atrial mixing if PGE1 administration is insufficient, and to alleviate hypoxemia ^[48]
    • Procedure: right heart catheterization with the creation or enlargement of an existing ASD
• Surgical repair: recommended within the first two weeks of life ^[49][50]
  • Arterial switch procedure: reversal of the aorta and pulmonary artery with insertion into the anatomically correct ventricle as well as correction of coronary artery supply ^[51][52]
  • Rastelli procedure ^[53][54]
    • Indication: TGV with concurrent large VSD and LVOTO repair
    • Procedure: creation of a conduit from the LVOTO through the VSD to the aorta and creation of a conduit from the RV to the pulmonary artery

Prognosis

• Without treatment, 90% of patients with TGA die within the first year of life. ^[55]
• Long-term survival beyond 15–20 years of age is ∼ 90%. ^[51]

Overview

• Definition
  • Absent or rudimentary tricuspid valve resulting in no blood flow between the RA and the RV
  • Patient survival is only possible if there are interatrial and interventricular communications (see “Other cardiac defects” below). ^[56]
• Other cardiac defects associated with tricuspid valve atresia
  • ASD
  • VSD
  • RV hypoplasia
  • Other defects (e.g., pulmonary outflow obstruction, aortic stenosis, aortic coarctation)

Epidemiology

• Prevalence: 0.2–1.2/10,000 live births in the US ^[16]
• Third most common cyanotic CHD

Pathophysiology

• Tricuspid atresia is accompanied by RV hypoplasia and RA dilation due to volume overload (univentricular heart).
• Circulation depends on the presence of interatrial and interventricular communications.
  • Blood in the RA flows through the ASD into the LA → venous blood mixes with arterial blood in the left heart → cyanosis
  • Blood can only reach the RV and pulmonary system via a VSD.

Clinical features

• Central cyanosis (occurs within days after birth)
• Tachypnea
• Cardiac examination findings
  • Holosystolic murmur at the lower left sternal border
  • Single S2
  • Jugular venous distention with a prominent A wave
  • Diminished peripheral pulses

Diagnostics

• Prenatal diagnosis: fetal echocardiography at 18–22 weeks' gestation ^[57]
• Imaging
  • Echocardiography (confirmatory test)
    • Absent tricuspid valve
    • ASD
    • RV hypoplasia
  • Chest x-ray
    • Mild cardiomegaly
    • Abnormal pulmonary markings
• ECG ^[58]
  • LVH with left axis deviation
  • Tall P waves
  • Minimal R waves in precordial leads
• Pulse oximetry: ↓ SpO₂

Treatment

• Initial postnatal management: cardiopulmonary stabilization until surgical palliation
  • PGE1 infusion
  • Cardiorespiratory support (e.g., inotropes, mechanical ventilation, supplemental oxygen)
• Surgical repair: three-stage surgical palliation to isolate both pulmonary and systemic circulations (see “Surgical repair” in “Hypoplastic left heart syndrome”)
• Optional temporary measures
  • In cases with concurrent pulmonary valve atresia or severe stenosis: systemic-to-pulmonary shunt (Blalock-Taussig shunt) to improve perfusion
  • Risk of pulmonary hypertension: pulmonary artery banding to control pulmonary hyperperfusion

Prognosis

• With surgery, ∼ 90% of patients live to the age of one year and the 10-year survival rate is ∼ 80%. ^[56]

Overview

• Definition: malformed tricuspid valve leaflets that are displaced into the right ventricle with subsequent tricuspid valve regurgitation and right heart enlargement (known as RV “atrialization”)
• Other cardiac defects associated with Ebstein anomaly
  • Interatrial communication (e.g., PFO, ASD): seen in ∼ 90% of patients ^[59]
  • Conduction disorders (e.g., Wolff-Parkinson-White syndrome, supraventricular tachycardia) ^[60]

Epidemiology

• Prevalence: 0.5–1/10,000 live births in the US ^[61]
• Accounts for < 1% of all CHD cases ^[16]

Etiology

• Multifactorial (most cases are sporadic) ^[62]
• Associated with prenatal lithium exposure ^[63][64]
• Isolated genetic defects (e.g., MYH7 which encodes β-myosin heavy chain)

Pathophysiology ^[59]

• Incomplete delamination (i.e., separation of valve tissue from the myocardium) during valve development can lead to one or more of the following:
  • Incomplete closure of the right atrioventricular valve and reduction in RV volume → tricuspid regurgitation→ RA dilation → right heart failure
  • RV atrialization → reduced function of the RV → insufficient systolic contraction → functional pulmonary valve atresia → ↓ pulmonary flow → ↓ cardiac output → systemic hypoperfusion, dyspnea, and fatigue
  • Bulging of the large sail-like anterior tricuspid leaflet into the RV → RVOTO → ↑ right heart pressure → ↑ flow through the patent foramen ovale → right-to-left shunt → cyanosis

Clinical findings ^[59]

• The clinical presentation of Ebstein anomaly varies according to the severity of the abnormality. ^[65]
  • Mild apical displacement → asymptomatic presentation throughout adulthood
  • Moderate tricuspid leaflet displacement → cyanosis or heart failure in infancy or childhood
  • Severe displacement → in utero heart failure → nonimmune hydrops fetalis → death
• Neonates and children
  • Cyanosis
  • Severe cardiomegaly and heart failure
  • Respiratory distress
• Adolescents and adults
  • Arrhythmias e.g., Wolff-Parkinson-White syndrome
  • Exertional dyspnea and fatigue
  • Palpitations and sudden cardiac death
• Cardiac examination findings
  • Loud S1
  • Widely split S1 and S2
  • Holosystolic murmur at the left sternal border

Diagnostics

• Prenatal diagnosis: fetal echocardiography
• Imaging
  • Echocardiography (confirmatory test)
    • Enlarged right heart
    • Tricuspid regurgitation
  • Chest x-ray
    • Mild to severe cardiomegaly
    • RA enlargement
  • MRI : apical displacement of the septal and posterior tricuspid leaflets
• ECG
  • Tall and broad P waves
  • First-degree atrioventricular block
  • Right axis deviation
  • Right bundle branch block
  • Findings specific for WPW syndrome (e.g., delta wave)
• Pulse oximetry: ↓ SpO₂

Treatment

• Initial postnatal management: stabilization of cardiorespiratory status until PVR decreases and surgery can be performed
  • PGE1 infusion
  • Inhaled nitric oxide or infusion of milrinone
• Surgical repair
  • Objective: creation of a systemic-pulmonary shunt, repair of the tricuspid valve, and reconstruction of the right ventricle
  • Age-related considerations
    • Neonates and infants: should be avoided in infancy and delayed as long as possible ^[66]
    • Children and adults: recommended if concomitant heart failure or progressive RV dysfunction is present ^[67]
• Arrhythmias: catheter ablation of the aberrant pathway ^[68]

Prognosis

• Varies according to the severity of disease
• Around 30% of patients die within the first year of life. ^[65]

Overview

• Definition: All four pulmonary veins drain into the systemic venous circulation (e.g., SVC, sinus venosus, RA, IVC) instead of the left atrium.
• Other cardiac defects associated with TAPVR: allow for right-to-left shunting and the mixing of deoxygenated and oxygenated blood
  • ASD
  • PDA

Epidemiology

• Prevalence: 0.6–1.2/10,000 live births in the US ^[16]

Etiology

• Multifactorial (may be associated with genetic alterations) ^[69]
• Associated with heterotaxy syndromes that involve asplenia ^[70][71]

Pathophysiology

The severity of symptoms and clinical presentation is determined by the following factors:

• Venous mixing: oxygenated pulmonary venous return mixes with the systemic venous system → right-to-left shunting of partially oxygenated blood via an interatrial connection (e.g., ASD, PFO, rarely PDA) into the systemic arterial circulation → cyanosis
• Pulmonary venous obstruction: obstruction of pulmonary venous return → ↑ pulmonary venous pressure → ↑ pulmonary edema → ↑ PVR → RVH, ventricular dilation, and heart failure

Clinical features ^[72]

• Cyanosis
• Respiratory failure
• Poor feeding and failure to thrive
• Hepatomegaly
• Cardiac examination findings
  • Fixed split S2; or loud S2
  • Systolic ejection murmur with diastolic rumble or mild to no murmur

Diagnostics

• Prenatal diagnosis: fetal echocardiography to detect abnormal pulmonary venous return ^[73]
• Imaging
  • Echocardiography (confirmatory test)
    • Malposition of pulmonary veins
    • Enlarged right heart
    • Right-to-left interatrial shunting
  • Chest x-ray
    • “Snowman sign” (seen in supracardiac TAPVR): the orientation of the heart and superior mediastinum appear as the shape of a snowman
    • Pulmonary hypervascularity
    • Right heart enlargement
• ECG ^[72]
  • Nonspecific findings
  • Right axis deviation due to RVH
• Pulse oximetry: ↓ SpO₂

Treatment

• Initial postnatal management: stabilization of cardiorespiratory status until surgery is performed (e.g., mechanical ventilation, supplemental O₂, inotropes)
• Surgical repair: recommended in all patients regardless of the severity of disease ^[74]

Prognosis

• With surgical correction, the long-term survival rate is 80–90%. ^[75]
• Without treatment, ∼ 80% of patients die within the first year of life. ^[76]

Overview

• Definition: underdevelopment of the aorticopulmonary septum → failure of the truncus arteriosus to divide into the aorta and pulmonary trunk → a single trunk that receives output from both ventricles
• Other cardiac defects associated with persistent truncus arteriosus
  • VSD
  • Interrupted aortic arch ^[77]
  • Coronary artery anomalies ^[78]

Epidemiology

• Prevalence: ∼ 1/10,000 live births in the US ^[16]

Etiology

• The failure of neural crest cells to migrate during the development of the cardiac outflow tract results in incomplete AP septum formation. ^[79]
• Associated with DiGeorge syndrome ^[80][81]

Pathophysiology

• Deoxygenated and oxygenated blood mix via the VSD → the truncus arteriosus receiving both RV and LV output → blood flow to both pulmonary and systemic circulations
• The severity of disease is determined by pulmonary vascular resistance (PVR).

Clinical features

• Cyanosis
• Respiratory distress
• Failure to thrive
• Cardiac examination findings
  • Bounding peripheral pulses
  • Harsh systolic murmur at the lower left sternal border
  • Loud S2

Diagnostics

• Prenatal diagnosis: fetal echocardiography ^[82]
• Imaging
  • Echocardiography (confirmatory test): single overriding great vessel arising from the heart
  • Chest x-ray
    • Right-sided aortic arch
    • ↑ Pulmonary vascular markings
    • Absent thymus, if associated with DiGeorge syndrome
• ECG: often normal and nonspecific findings
• Pulse oximetry: ↓ SpO₂

Treatment

• Initial medical management: stabilization of cardiopulmonary function (e.g., diuretics, dopamine, ventilation, correction of metabolic acidosis) ^[9]
• Surgical repair: Surgical correction is recommended in the neonatal period. ^[83][84]

Prognosis

• With surgical repair, the 30-year survival rate is ∼ 70%. ^[85]

Overview

• Definition: spectrum of disease consisting of severe hypoplasia of the left ventricle with possible stenosis and/or atresia of the mitral valve, aortic valve, or aortic arch ^[86]

Epidemiology

• Extremely rare (2–3/10,000 live births in the US ^[16][87]
• Sex: ♂ > ♀ (1.5:1) ^[88]
• Although rare, HLHS is responsible for 25–40% of all neonatal cardiac deaths. ^[89]

Etiology

• Multifactorial: associated with single gene polymorphisms, altered blood flow patterns, and intrauterine infection ^[90][91][92]
• Syndromic associations: trisomy 13, trisomy 18, Jacobsen syndrome, and Turner syndrome ^[93][94]

Pathophysiology

• The hypoplastic left ventricle is nonfunctional, resulting in the RV becoming the primary supply for pulmonary and systemic circulations.
• Survival depends on the presence of a PDA (right-to-left shunt); and an ASD.

Clinical findings

• May be asymptomatic at birth if the open PDA provides adequate systemic perfusion
• Aggravation of symptoms following closure of the PDA
• Postnatal cyanosis (not corrected by supplement O₂)
• Tachypnea
• ↓ BP, ↓ peripheral pulses, and cool extremities
• Heart failure and cardiogenic shock
• Cardiac examination findings
  • Typically no murmur
  • Loud, single S2

Diagnostics

• Prenatal diagnosis: fetal echocardiography ^[95]
• Imaging
  • Echocardiography (confirmatory test): visualization of absent or hypoplastic LV
  • Chest x-ray: variable and nonspecific findings
• ECG: typically normal
• Pulse oximetry: ↓ SpO₂

Treatment

• Initial medical management: continuous PGE1 infusion prior to heart surgery ^[96]
• Surgical repair: Palliative surgery is used in single-ventricular cardiopathologies. ^[88]
  • Three-step staged surgical correction
    • Norwood procedure (stage I): performed while the patient is a neonate ^[97][98]
    • Glenn procedure (stage II): performed at ∼ 3–6 months of age ^[99]
    • Fontan procedure (stage III): performed after 2–3 years of age ^[100]
  • Alternative: heart transplant ^[101]

Prognosis

• Even with surgical correction, the 5-year survival rate remains low (∼ 65%). ^[97]
• For patients that survive to one year of age, long-term survival (up to 18 years of age) is ∼ 90%. ^[102][103]