Acyanotic congenital heart defects

Acyanotic heart defects are congenital cardiac malformations that affect the atrial or ventricular walls, heart valves, or large blood vessels. Common causes include genetic defects (e.g., trisomies), maternal infections (e.g., rubella), or maternal use of drugs or alcohol during pregnancy. Acyanotic heart defects are pathophysiologically characterized by a left-to-right shunt, which causes pulmonary hypertension and right heart hypertrophy. The symptoms depend on the extent of the malformation and the resulting impairment of cardiac function. Infants may be asymptomatic or present with exercise intolerance, failure to thrive, and symptoms of heart failure. Characteristic heart murmurs are important clues for establishing the diagnosis, which is typically confirmed by visualizing the defect on echocardiography. Chest x-ray, MRI, or cardiac catheterization may also be required to determine indications for surgery and plan the procedure. Acyanotic heart defects requiring treatment are repaired via catheter procedures or surgery. Supportive medical therapy is required in cases of heart failure (e.g., diuretics, inotropic agents) or if surgery cannot be performed (e.g., prostaglandin). Common complications include arrhythmias, embolisms, and infective endocarditis, especially if treatment is delayed.

Commonly associated conditions and risk factors

General pathophysiological processes ^[1]

• Congenital heart defects (CHDs) are caused by the disruption of the normal sequence of cardiac morphogenesis.
• CHDs may lead to the formation of pathological connections (shunts) between the right and left heart chambers, allowing blood to flow along the pressure gradient from high pressure to low pressure.
• The shunts are classified according to the direction of the blood flow as either left-to-right or right-to-left.
  • Left-to-right shunt: oxygenated blood from the lungs is shunted back into the pulmonary circulation via an atrial septal defect (ASD), ventricular septal defect (VSD), or patent ductus arteriosus (PDA) → pulmonary hypertension and right ventricular pressure overload → right-sided heart hypertrophy (cardiomegaly on x-ray) and heart failure but no cyanosis
  • Right-to-left shunt: blood flows from the right to the left heart via a shunt → deoxygenated blood entering the systemic circulation → cyanosis
• Eisenmenger syndrome (can occur at any age, but usually develops during late stages of CHDs)
  1. Prolonged pulmonary hypertension due to a left-to-right shunt causes reactive constriction with permanent remodeling of pulmonary vessels → irreversible pulmonary hypertension
  2. Right ventricle hypertrophies to compensate for pulmonary hypertension → right ventricular pressure increasing and eventually exceeding left ventricular pressure → reversal of blood flow → onset of cyanosis (either at rest or during exercise), digital clubbing, and polycythemia

Pulmonary arterial hypertension (Eisenmenger syndrome) may cause untreated left-to-right shunts (acyanotic heart defects) to progress to right-to-left shunts (cyanotic defects) if right ventricular pressure exceeds left ventricular pressure.

Left-to-Right shunts = LateR cyanosis. Right-to-Left shunts = eaRLy cyanosis.

General clinical features

For specific features, see “Clinical features” in the subsections below.

• Nonspecific findings
  • Normal skin tone
  • Exercise intolerance
    • Fatigue, pallor, and diaphoresis (sweating)
    • Tachycardia
    • Dyspnea
    • Grunting, nasal flaring, retractions, and/or head bobbing may be seen ^[2]
  • Failure to thrive
  • Recurrent bronchopulmonary infections
• Heart failure
  • Right heart failure
    • Hepatic venous congestion with hepatomegaly
    • Peripheral edema is rarely seen in infants. ^[3]
  • Left heart failure
    • Tachypnea, pulmonary edema
    • Low cardiac output: ↓ blood pressure, pallor, sweating, cool extremities, syncope
• Differential cyanosis: cyanosis in the lower extremities if Eisenmenger syndrome occurs (seen in patients with PDA)

General treatment considerations

• General measures: nutritional support and immunoprophylaxis
• Ductal-dependent CHDs: Infusion of prostaglandin (PGE1) to prevent closure of the ductus arteriosus (see “Overview of cyanotic congenital heart defects”).
• Heart failure
  • Diuretics or ACE inhibitors to decrease fluid volume and lower pulmonary vascular resistance
  • Inotropic agents (e.g., digoxin) to improve contractility of the heart
• Antibiotic prophylaxis
  • Not generally recommended before procedures
  • Used for 6 months after surgical correction procedures and if small defects remain following repair ^[4][5]
• Surgery:
  • Correction of defect should be considered in symptomatic patients who have not responded to therapeutic management
  • If Eisenmenger syndrome has occurred: heart-lung transplant or lung transplant

The “3 Ds” of acyanotic CHDs (in order of frequency): VSD, ASD, PDA

Epidemiology

• The most common congenital heart defect (∼ 4/1,000 live births) ^[6]
• Occurs as an isolated heart defect or in combination with others (e.g., with AVSD, tetralogy of Fallot, TGA)

Etiology

• Genetic syndromes
  • Most commonly: Down syndrome, Edward syndrome, Patau syndrome
  • Less commonly: Cri-du-chat syndrome, Apert syndrome (a rare autosomal dominant disorder that manifests with craniofacial anomalies and fusion of the fingers and toes. )
• Intrauterine infections (e.g., TORCH)
• Maternal risk factors: diabetes, obesity, smoking ^[6]

Pathophysiology

• Localization: most commonly in the membranous part of the ventricular septum (pars membranacea)
• Defect in ventricular septum → left-to-right shunt with the following consequences:
  • RV volume overload → RV eccentric hypertrophy
  • Excessive pulmonary blood flow → increased pulmonary artery pressure → pulmonary hypertension
  • Decreased cardiac output
  • LV volume overload → LV eccentric hypertrophy
  • ↑ O₂ saturation in right ventricle and pulmonary artery

Clinical features ^[7]

• Small defects: usually asymptomatic
• Medium-sized or large defects
  • Lead to heart failure by the age of 2–3 months
  • Become symptomatic after high pulmonary vascular resistance (PVR) present at birth starts to decrease: ↓ PVR → ↓ right ventricular pressure → ↑ left-to-right shunt → symptoms
  • See “Nonspecific findings” and “Heart failure” in “Overview” above.
• Hyperdynamic precordium may be detected in hemodynamically relevant defects.
• Harsh holosystolic murmur over the left lower sternal border
  • Becomes more intense with maneuvers that increase left ventricular afterload (e.g., handgrip)
  • Typically louder in small defects
• Mid-diastolic murmur over cardiac apex
• Systolic thrill
• Loud pulmonic S₂ (if pulmonary hypertension develops)

Symptoms of heart failure in children with VSD only develop when PVR decreases to adult levels and thus allows left-to-right shunting to occur.

Diagnostics ^[7]

• Echocardiography (confirmatory test)
  • To assess defect size and shunt volume
  • Doppler ultrasound findings of pathological left-to-right blood flow can help diagnose minor ventricular defects.
• ECG
  • Small defects: normal ECG findings
  • Medium-sized or large defects
    • Signs of LV hypertrophy (due to volume loading): ↑ QRS amplitude, left axis deviation, left atrial enlargement
    • Signs of RV hypertrophy (due to pulmonary hypertension or obstruction of the pulmonary outflow tract): vertical or right axis deviation, P pulmonale, PR prolongation, complete or incomplete right bundle branch block
• Chest x-ray
  • Enhanced pulmonary vascular markings
  • Left atrial and ventricular enlargement
  • In later stages, enlarged right ventricle and pulmonary artery (due to elevated PVR)

Treatment ^[5][7]

• Small defects often heal spontaneously and rarely require surgical interventions (follow-up echocardiography is recommended)
• Symptomatic and large defects
  • See “General treatment considerations” in “Overview” above.
  • Surgical (patch) repair
    • In children < 1 year of age with signs of pulmonary hypertension
    • In older children who have not improved with medical therapy
    • Closure of a VSD results in a decrease in right ventricular and left atrial pressures and an increase in left ventricular pressure when compared to pre-treatment values
  • If Eisenmenger syndrome has occurred: heart-lung transplant or lung transplant with concurrent VSD repair

Complications

• Arrhythmias
• Heart failure
• Eisenmenger syndrome
• Infective endocarditis
• Aortic regurgitation

Epidemiology

• Second most common CHD (∼ 2/1,000 live births)
• Sex: ♀ > ♂

Etiology

• Down syndrome
• Fetal alcohol syndrome
• Holt-Oram syndrome (hand-heart syndrome)
  • Autosomal dominant disorder
  • Characterized by ASD, a first-degree heart block, and abnormalities of the upper limbs (e.g., absent radial bones)
  • Affects ∼ 1/100,000 children

Pathophysiology

• Impaired growth or excessive resorption of the atrial septa in utero leads to atrial septal defects (absent atrial septa tissue).
  • Ostium primum atrial septal defect (ASD I): ∼ 15–20% (usually accompanied by other heart defects)
  • Ostium secundum atrial septal defect (ASD II): ∼ 70% (usually isolated)
• Typically a low-pressure, low-volume, minor left-to-right shunt (therefore, patients are asymptomatic)
• ASD → oxygenated blood shunting from LA to RA → ↑ O₂ saturation in the RA → ↑ O₂ saturation in RV and pulmonary artery
• In more severe defects, the shunts may lead to supraventricular arrhythmias, pulmonary hypertension, and/or Eisenmenger syndrome.

Clinical features

• Depend on defect size and shunt volume
  • Small defects: usually asymptomatic
  • Medium-sized to large defects
    • Symptoms can vary from asymptomatic to heart failure.
    • ASDs typically manifest with advancing age. ^[8]
• Systolic ejection murmur over the second left ICS sternal border
• Widely split second heart sound (S₂) over the second left ICS, which is fixed (does not change with respiration )
• Soft mid-diastolic murmur over the lower left sternal border
• See “General clinical features” above.

Diagnostics ^[9]

• Echocardiography (confirmatory test): interatrial communication, best visualized in the apical four-chamber and subcostal views
• ECG: signs of RV hypertrophy (vertical or right axis deviation, P pulmonale, PR prolongation, complete or incomplete right bundle branch block)
• Chest x-ray
  • Enlarged right atrium, ventricle, and pulmonary arch
  • Enhanced pulmonary vasculature

Treatment ^[10]

• In children with ASD, spontaneous closure may occur.
• Patch repair
  • Indicated in symptomatic children with a significant left-to-right shunt
  • Surgical or via percutaneous transcatheter procedure

Complications ^[11]

• Paradoxical embolism (↑ risk of ischemic stroke): small blood portions from inferior vena cava bypass pulmonary circulation → direct emptying into left atrium → paradoxial embolism and stroke in the case of thromboembolism
• Heart failure

Epidemiology

• Prevalence: 25–30% of the general population

Etiology

• Associated with Loeys-Dietz syndrome

Pathophysiology

• Failure of the atrial septum primum to fuse with the septum secundum following birth → persistence of foramen ovale; → mild left-to-right shunt
• A shunt reversal may be induced by certain maneuvers that increase right atrial pressure (e.g., Valsalva maneuver, coughing).

ASD = Septal tissue Deficiency. PFO = enough tissue, but Problems with Fusion.

Clinical features

• Affected individuals are usually asymptomatic until complications occur (see below).

Diagnostics

• Often an incidental finding
• If ischemic stroke occurs
  • Contrast echocardiography (best initial and confirmatory test): to evaluate defect size and shunt volume
  • Transesophageal echocardiography: if contrast echocardiography findings are negative

Treatment

• Asymptomatic PFO: Treatment is not usually required.
• Ischemic infarction in patients with confirmed PFO
  • Antiplatelet agents or anticoagulation
  • Surgical or percutaneous closure of the defect

Complications

• Paradoxical embolism
• Stroke ^[12]
• Systemic embolisms (e.g., renal infarction)

PFO may not be causally related to stroke. Screening for DVT and other causes is still important.

Definition

• Failure of the ductus arteriosus to completely close postnatally

Epidemiology

• Incidence: ∼ 5/10,000 full-term births
• In premature infants: 20–60% ^[13]
• Sex: ♀ > ♂ (2:1) ^[4]
• Isolated heart defect in 90% of cases

Etiology

• Prematurity
• Maternal exposure during pregnancy
  • Rubella infection (during the first trimester of pregnancy)
  • Alcohol consumption
  • Phenytoin use (fetal hydantoin syndrome)
  • Prostaglandin use
• Respiratory distress syndrome
• Trisomies (e.g., Down syndrome)

Pathophysiology

• Ductus arteriosus enables the underdeveloped lungs to be bypassed by the fetal circulation (normal right-to-left shunt) and remains patent in utero via PGE and low O₂ tension.
• After birth, pulmonary vascular resistance decreases and thus allows for the reversal of the shunt from right-to-left to left-to-right.
• Failure of the ductus arteriosus to close after birth → persistent communication between the aorta and the pulmonary artery → left-to-right shunt → volume overload of the pulmonary vessels → continuous RV (and/or LV) strain → heart failure (see also “Overview” above)
• Eisenmenger syndrome may occur with shunt reversal and manifest with differential cyanosis.

Clinical features

• Small PDA: asymptomatic with normal findings on physical examination
• Large PDA
  • Nonspecific symptoms (e.g., failure to thrive); and symptoms of heart failure in infancy (see the “Overview” above)
  • Heaving, laterally displaced apical impulse
  • Bounding peripheral pulses, wide pulse pressure ^[14]
  • Machinery murmur: loud continuous murmur heard best in the left infraclavicular region and loudest at S₂

PDA comes with Prolonged Deafening Auscultation findings.

Diagnostics ^[14]

• Echocardiography (confirmatory test)
  • Findings can show left cardiac enlargement
  • Used to assess shunt volume and pulmonary artery pressure
  • Color doppler: Findings can show blood flow from the aorta into the pulmonary artery.
• ECG
  • Normal findings in small PDA
  • Left axis deviation due to LVH seen in large PDA
• Chest x-ray
  • Prominent pulmonary artery and aortic knob at the upper left heart border
  • Increased pulmonary markings
• Cardiac catheterization and angiography: only necessary prior to repair or in more complex CHDs

Treatment ^[15]

• Observation: regular heart and pulmonary vasculature evaluation in patients with small PDAs and no evidence of left-sided heart volume overload
• Elective ductal closure
  • Indications for closure
    • Symptomatic PDAs
    • Left heart enlargement; or mild to moderate pulmonary hypertension
  • Techniques
    • Pharmacological closure (in premature infants): infusion of indomethacin or ibuprofen
      • Inhibiting the prostaglandin synthesis with indomethacin or ibuprofen induces the closure of the ductus in preterm infants.
      • Contraindicated in active intraventricular hemorrhage
    • In infants > 5 kg: percutaneous catheter occlusion or surgical ligation
• Administer prostaglandin (PGE1) to keep the PDA open if needed for survival (e.g., in transposition of the great vessels, tetralogy of Fallot, hypoplastic left heart).

Complications ^[14]

• Heart failure in infancy
• Infective endocarditis
• Common cause of pulmonary hypertension and Eisenmenger syndrome in adolescents and adults
• Differential cyanosis

Definition

• Narrowing of the aorta at the aortic isthmus, which is a distal part of the aortic arch, close to the ductus arteriosus (juxtaductal) and left subclavian artery
• Rarely, the coarctation is located in the thoracic or abdominal aorta

Epidemiology ^[16]

• Prevalence: 4/10,000 live births
• Sex: ♂ > ♀

Etiology ^[17]

• Congenital
  • The exact etiology is unclear
  • Two etiological theories have been developed.
    • Hemodynamic: caused by underdevelopment of the aorta due to an abnormally decreased antegrade intrauterine blood flow
    • Ductal: caused by closure of the ductus arteriosus tissue that extends into the thoracic aorta
  • Associated with Turner syndrome (in 5–15% of female patients with coarctation) ^[18][19]
  • Often accompanied by a bicuspid aortic valve , VSD, and/or PDA
• Acquired: e.g., Takayasu arteritis, severe atherosclerosis

Pathophysiology ^[17]

• Genetic defects and/or intrauterine ischemia → medial thickening and intimal hyperplasia forming a ridge encircling the aortic lumen → narrowing of the aorta → ↑ flow proximal to the narrowing and ↓ flow distal to the narrowing
  • In preductal (infantile) type (most common type), the narrowing is proximal to the ligamentum arteriosum or ductus arteriosus.
  • In postductal (adult) type, the narrowing is distal to the ligamentum arteriosum or ductus arteriosus.
• In cases of discrete stenosis: Left ventricular outflow obstruction → myocardial hypertrophy and increased collateral blood flow (e.g., intercostal vessels, scapular vessels).
• In long segment stenosis, compensatory mechanisms do not develop → closure of PDA after birth → left ventricular pressure and volume overload → hypoperfusion of organs and extremities distal to the stenosis ^[20]

Clinical features ^[17]

• Asymptomatic as long as PDA is present or if aortic narrowing is mild
• Differential cyanosis: cyanosis of the lower extremities (when the left subclavian artery outflow is involved, cyanosis might also be seen in the left arm)
• Brachial-femoral delay: weak femoral pulses
• ↑ Blood pressure (BP) in upper extremities and ↓ BP in lower extremities
  • If distal narrowing of the left subclavian artery: ↑ BP in both arms and ↓ BP in both legs
  • If origin of left subclavian artery is involved: BP in the right arm > left arm.
• Cold feet and lower-extremity claudication upon physical exertion
• Systolic ejection murmur over left posterior hemithorax and/or continuous murmur below left clavicula and between the shoulder blades
• Strong apical impulse displaced to the left
• Headache, epistaxis, tinnitus
• In severe stenosis: See “Nonspecific findings” and “Heart failure” in “Overview” above.
• In severe stenosis: shock and multiorgan failure when ductus arteriosus closes

Diagnostics ^[17]

• Blood pressure measurements
  • Best initial test
  • BP measurements for upper and lower extremities to check for brachial-femoral delay
• Pulse oximetry: ↓ SpO2
• Doppler echocardiography (confirmatory test): location and extent of stenosis; detection of concurrent anomalies (VSD, PDA, bicuspid aortic valve)
• X-ray
  • Cardiomegaly and ↑ pulmonary vascular markings
  • Figure of 3 sign: the result of an hourglass-like narrowing of the aorta caused by pre- and postdilatation of the aorta with an indentation at the site of coarctation
  • Rib notching: a radiographic sign caused by collateral circulation between the internal thoracic and intercostal arteries.
    • Enlarged vessels compress the neighboring ribs and lead to their pressure atrophy.
    • Classically affects the inferior border of the 3^rd– 8^thribs
• MRI or CT
  • In complicated cases and in adults
  • To determine the length of coarctation and for intervention planning
• Genetic testing: for Turner syndrome

Treatment ^[21]

• Initial management: infusion of prostaglandin (PGE1)
• Surgical correction; or balloon angioplasty: for most patients < 5 years of age. Older patients may have a transcatheter intervention with stent placement.
• Follow-up and monitor for restenosis, aortic aneurysm, and aortic dissection.

Complications

• Secondary hypertension
• Aortic dissection and rupture
• Berry aneurysm → cerebral hemorrhage ^[22]
• Heart failure
• Infective endocarditis

Definition ^[23]

• Defect of atrioventricular valves (i.e., mitral and tricuspid valves) as well as the atrial and/or ventricular septum
  • Complete form: ASD and VSD, common AV valve
  • Partial form: only ASD and minor AV valve abnormalities

Etiology

• Strongly associated with Down syndrome ^[23][24]
• Association with maternal diabetes and obesity has been shown in some studies. ^[25]

Pathophysiology ^[23]

• Complete form (ASD and VSD) → atrial and ventricular left-to-right shunt → excessive pulmonary blood flow and biventricular volume overload → pulmonary hypertension and heart failure
• Partial form (ASD only) → atrial left-to-right shunt → symptoms that may remain minimal until adulthood
• In both forms: abnormal AV valve → AV valve regurgitation → in utero heart failure (nonimmune hydrops fetalis)

Clinical features ^[23]

• Complete form: See “Nonspecific findings” and “Heart failure” in “Overview” above.
• Partial form: See “Clinical features” in “Atrial septal defect (ASD)“ above.

Diagnostics ^[23]

• Antenatal echocardiography: findings of endocardial cushion defect in first trimester → screening for Down syndrome
• Echocardiography (confirmatory test): to assess defect size, shunt volume, and global cardiac function
• ECG: left axis deviation due to LVH
• Chest x-ray
  • Complete form: global cardiomegaly, ↑ pulmonary markings
  • Partial form: enlarged right heart and pulmonary artery

Treatment ^[26]

• Improve cardiac function in patients with heart failure (see “General treatment considerations” for heart failure in “Overview” above).
• Surgical repair

Epidemiology

• Relatively common in the general population (7–12% of all CHDs) ^[27]
• Usually congenital (rarely acquired )

Pathophysiology

• Pulmonary valve stenosis → right ventricular outflow obstruction → pressure overload → right ventricular hypertrophy

Clinical features

• Depending on the grade of stenosis, symptoms of heart failure may occur.
• Systolic murmur heard best over the second left ICS at the sternal border
• S₂ wide splitting

Diagnostics

• Echocardiography (confirmatory test): to assess the severity of stenosis
• Chest x-ray: Findings in adults with isolated pulmonary stenosis show a prominent pulmonary artery segment.

Treatment

• Transcatheter dilatation of the pulmonary valve
  • Indication: prestenotic to poststenotic pressure gradient > 50 mm Hg
  • Technique: balloon pulmonary valvuloplasty
• Surgery: commissurotomy if balloon dilatation is not possible

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