Acyanotic Congenital Heart Disease:Left-to-Right Shunt Lesions

Jamie N. Colombo, DO,* Michael A. McCulloch, MD*

*Department of Pediatrics, Division of Pediatric Cardiology, University of Virginia Children’s Hospital, Charlottesville, VA

Education Gap

An understanding of the pathophysiology, diagnosis, and appropriate initial

management of acyanotic congenital heart disease is needed to

appropriately care for infants in the NICU.

Abstract

Acyanotic congenital heart diseases or left-to-right shunting lesions are the

most common form of congenital heart disease. Although most resolve

spontaneously, many will remain hemodynamically significant, particularly in

the premature infant. Understanding the difference in pathophysiology,

diagnosis, and management between the term and preterm infant is

imperative to minimize the risk of secondary organ dysfunction and ensure

proper growth and development.

Objectives After completing this article, readers should be able to:

1. Explain the pathophysiology, initial presentation, andmanagement of left-

to-right pre-tricuspid shunt lesions.

2. Explain the pathophysiology, initial presentation, andmanagement of left-

to-right post-tricuspid shunt lesions.

3. List the genetic mutations associated with the different left-to-right shunt

lesions.

4. Differentiate the effects of these lesions on term and preterm infants.

INTRODUCTION

Congenital heart disease (CHD) is the most common genetic abnormality, with

an incidence that increases from approximately 8 per 1,000 term births to 12.5

per 1,000 premature births. (1)(2)More important, however, are the significantly in-

creased hemodynamic consequences of CHD in preterm infants compared with

their term peers. This review will focus on acyanotic CHD defined as an anatomic

connection between the pulmonary and systemic circulations in which oxygenated

AUTHOR DISCLOSURE Drs Colombo andMcCulloch have disclosed no financialrelationships relevant to this article. Thiscommentary does not contain a discussionof an unapproved/investigative use of acommercial product/device.

ABBREVIATIONS

ASD atrial septal defect

AVSD atrioventricular septal defect

CHD congenital heart disease

ECG electrocardiography

PDA patent ductus arteriosus

PVR pulmonary vascular resistance

Qp pulmonary blood flow

Qs systemic blood flow

SVR systemic vascular resistance

VSD ventricular septal defect

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systemic blood flow on the left side of the heart shunts to the

partially deoxygenated pulmonary bloodflowon the right side

of the heart. The vast array of acyanotic heart lesions will

be grouped into 2 physiologic subtypes of pre-tricuspid valve

and post-tricuspid valve shunting. Further consideration will

be given to gestational age when appropriate.

PRE-TRICUSPID VALVE SHUNTS

The physiologic distinction of pre-tricuspid valve shunts de-

scribes shunting across an atrial septal defect (ASD) during

ventricular diastole and atrial systole. The direction of flow

across an atrial communication is dictated by differences in

ventricular compliance. Ventricular compliance can change

when chronic atrial contraction occurs into a ventricle that

has become stiff and noncompliant either from myopathic

changes (ie, hypertrophic cardiomyopathy) or from chroni-

cally elevated afterload (ie, pulmonary/aortic valve stenosis

or elevated pulmonary or systemic vascular resistance).

Shortly after birth, ASD shunt magnitude is low because

neonatal right ventricular stiffness and compliance are very

similar to those in the left ventricle. With physiologic de-

clines in pulmonary vascular resistance, compensatory in

utero right ventricular hypertrophy regresses, resulting in a

more compliant right ventricle and atrium. This allows a

progressive left-to-right increase in ASD shunt volume that

is further pronounced with larger defect size. (3) ASDs are

considered volume-loading defects to the right heart (as

opposed to pressure-loading defects; see Post-Tricuspid

Valve Shunts section), with larger defects producing right

atrial and ventricular dilation.

IncidenceExcluding patent foramen ovale, which persists in up to 35%

of adults, ASDs exist in approximately 1 in 1,500 children,

comprise 6% to 10% of all cardiac anomalies, (4) and are

the most commonly recognized mutation in nonsyndromic

CHD. (5) Although ASDs frequently occur with other con-

genital heart lesions, isolated ASDs have been associated with

NKX2.5,GATA4,GATA6, andTBX20mutations.Mutations in

the TXB5 gene are associated with Holt-Oram syndrome.

Several anatomic classifications of atrial defects can occur

in uterowhen the septumprimumand septum secundumdo

not appropriately fuse with each other, the endocardial cush-

ions, and posterior aspect of the atria. Ostium secundum type

defects compose 75% of all ASDs and are essentially identical

to a patent foramen ovale with the major distinction being

size. (4) The foramenovale is a critical connectionmaintained

throughout fetal life, directing oxygenated ductus venosus

blood across its opening to the left atrium, left ventricle,

preductal aortic vessels, and the developing brain. Primum

ASDs exist in the setting of atrioventricular septal defects

(AVSDs) but their physiologic presentation is typically deter-

mined more by the associated lesions. Sinus venosus type

ASDs comprise 4% to 11% of all ASD types and are com-

monly associated with anomalous return of at least 1 pulmo-

nary vein, resulting in a significantly larger left-to-right

shunt. (6) Coronary sinus ASDs not only produce ASD phys-

iology but are commonly associated with systemic desatu-

ration as they functionally “unroof” the coronary sinus,

adding markedly desaturated blood into the left atrium.

DiagnosisASDs are rarely associated with clinical findings in the term

neonate. At 2 to 3 years of age, classic findings include a

widely split S2 and a systolic ejection murmur along the left

sternal border because of increased flow across the pulmo-

nary valve. Echocardiography is the diagnostic tool of choice

(Fig 1). Chest radiography may show an enlarged cardiac

silhouette and increased pulmonary vascular markings, but

this can be difficult to appreciate in an infant with lung

disease. Electrocardiography (ECG) will show right ventric-

ular hypertrophy and right axis deviation, but this is true in

all newborns and is usually not helpful.

ManagementTerm neonates with isolated ASDs are typically asymptom-

atic and rarely require intervention. Should the patient

develop significant signs of congestion with increased work

of breathing, tachypnea, hepatomegaly, and poor growth,

diuretics are the first-line treatment. As such, ASD closure

is not common until at least 2 years of age, with both de-

vice closure in the catheterization laboratory and surgical

closure having excellent results. (7)(8)

Premature InfantsThe premature infant with chronic lung disease represents

a unique challenge. When subjected to chronic hyperoxia

and positive pressure ventilation, the immature lung paren-

chyma exhibits alveolar simplification. (9) The subsequent

reduced number of alveoli renders these infants particularly

sensitive to any increase in pulmonary blood flow, par-

ticularly when coupled with aspiration, inflammation, or

acquired pulmonary vein stenosis, all of which result in

congestion from increased intra-alveolar fluid. Therefore,

premature infants not following the expected perinatal

course (ie, respiratory distress out of proportion to their

lung disease) who have an ASD deemed amenable to device

closure in the cardiac catheterization laboratory should be

considered for this therapy to improve outcomes. (10)(11)

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POST-TRICUSPID VALVE SHUNTS

Left-to-right shunting lesions distal to the tricuspid valve

include various ventricular septal defects (VSDs; eg, peri-

membranous VSD and atrioventricular canal defects) and

systemic to pulmonary shunts (eg, patent ductus arteriosus

[PDA] and aortopulmonary window). The hemodynamic

significance of a shunt depends on the size and resistance

within the defect, and the relationship between pulmonary

vascular resistance (PVR) and systemic vascular resistance

(SVR). Inutero and immediately after birth, thePVRand SVR

are approximately equal, producing a PVR/SVR ratio of 1:1.

After a healthy newborn takes the first breath, the pulmonary

vascular bed is exposed to oxygen, promoting pulmonary

arteriolar relaxation and a progressive decrease in the PVR/

SVR ratio. PVR reaches its nadir between 8 weeks and 6

months of age, resulting in a PVR/SVR ratio of 0.2:1 or less.

Regardless of the size and resistance within a post-tricuspid

valve communication, net shunting of blood will not occur

until the PVR/SVR ratio has deviated significantly from 1:1

(ie, an increase in pulmonary blood flow relative to systemic

blood flow cannot occur until PVR is less than SVR).

The PVR/SVR ratio effectively acts as the second in a

series of 2 resistors, with the first being the communication

itself. The Hagen-Poiseuille equation states that resistance

to flow across a vessel is directly related to its length and

inversely related to its radius to the fourth power (R¼ L/ r4).

VSDs have no length and act as a static resistor in the

neonate, therefore, the resistance to flow across the VSD is

entirely determined by the radius or size of the defect. By

comparison, a PDA has significant length and its radius is

affected by both contraction of oxygen-sensitive ductal tissue

and angulations within a tortuous ductus. However, the

relative resistance that exists within the pulmonary and

systemic vascular beds is markedly greater than that found

within the defects themselves, and is subsequently the

largest determinant of shunting volume and direction.

These complex interactions ultimately determine whether

a post-tricuspid valve shunting lesion produces a pressure

and/or volume burden on the heart and lungs.

VSD shunting occurs exclusively during systole. Large

nonrestrictive VSDs are associated with pulmonary arterial

pressures identical to systemic arterial pressures, regardless

of the PVR/SVR ratio. This is because pressure generation

within a vascular bed is the product of its vascular resistance

(PVR and SVR) and pulmonary (Qp) and systemic (Qs)

blood flow ejected into that bed. For example, if the ratio of

resistance is 1:1, there is no net shunting (Qp:Qs ¼ 1:1), but

if the PVR/SVR ratio is 0.5:1 and the Qp:Qs is 2:1, the

pulmonary circulation is exposed to twice as much blood

flow as is the systemic circulation.

VSDs in the setting of a low PVR/SVR ratio (ie, <0.5:1)

produce a volume burden on both the lungs and left

ventricle. Excess pulmonary blood flow shunted from the

left ventricle combines with the right ventricular output and

produces hydrostatic pressures that overwhelm oncotic

forces, resulting in intra-alveolar water or pulmonary

edema. This total blood volume must then return to the

left atrium and ventricle, progressively dilating both cham-

bers. Newborns with such ventricular level shunting

become increasingly tachypneic, intolerant of oral feedings,

and fail to thrive, producing the classic presentation of

congestive heart failure. This rate of decline is reduced with

smaller defects and if the PVR/SVR is closer to 1:1. Large,

Figure 1. Subcostal echocardiogram of a secundum atrial septal defect (indicated by arrow) with and without color. LA¼left atrium; LV¼left ventricle;RA¼right atrium; RV¼right ventricle.

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long-standing, unrepaired VSDs cause progressive pul-

monary arteriolar vasoconstriction and PVR elevation that

eventually becomes irreversible, resulting in Eisenmenger syn-

drome; this is exceedingly rare in the first few years of age.

Although the length of a PDA directly increases resis-

tance, compared with a large VSD, PDAs typically produce a

larger volume burden on the pulmonary vascular bed for 2

reasons. First, a newborn’s ductus arteriosus is large, with a

cross-sectional area equal to the descending aorta, largely

counteracting the resistance effect of its length. Second,

shunting occurs throughout both systole and diastole.

VENTRICULAR SEPTAL DEFECT

IncidenceVSDs are themost common form of CHD, representing 20%

to 30% of isolated lesions and occurring in 1.3 to 3.9 of 1,000

live births. (12)(13) VSDs are classified as 4 types, with perimem-

branous VSDs being the most common. (14) Isolated VSDs are

the most common CHD seen in patients with trisomy 21, 18,

and 13, but only 5% to 8% of patients with an isolated VSD

will have a chromosomal disorder. (13)TBX5,GATA4, andNKX2

mutations have been associated with isolated VSDs. (13)

DiagnosisSmall, restrictive VSDs are often found incidentally with a

holosystolic murmur at the left sternal border, but only after

PVR has begun to fall. Because of the lack of flow acceler-

ation and associated murmur, large defects may not become

clinically evident until an infant becomes symptomatic, as

described earlier. Chest radiography may show signs of

pulmonary congestion and an enlarged cardiac silhouette.

An ECG may show signs of left and right ventricle hyper-

trophy with disease progression, but are typically not diag-

nostic. Echocardiography is the diagnostic tool of choice

(Fig 2) and additional testing is not usually indicated.

ManagementUp to 45% of VSDs spontaneously close during the first year

of age. (12) For those that become hemodynamically signif-

icant, surgical closure is the primary option, depending on

the location of the defect and size of the child, with low

morbidity and mortality rates and excellent outcomes. (12)

Premature infants with VSDs are particularly challenging

because their incomplete pulmonary arteriolar development

produces an extremely compliant pulmonary vascular bed,

resulting in an earlier onset of pulmonary overcirculation

and congestive heart failure. This is further complicated

in patients with chronic lung disease. Pulmonary artery

banding may be considered if there are multiple defects

within the ventricular septum or if the infant’s size or

gestational age precludes cardiopulmonary bypass. (12)

ATRIOVENTRICULAR SEPTAL DEFECT

IncidenceAVSDs comprise a wide variety of congenital heart lesions

involving endocardial cushion formation. The spectrum

ranges from partial defects with a primum ASD and mitral

valve cleft (most common type) to a complete defect with an

ASD, VSD, and single atrioventricular valve to an unbalanced

AVSD with heterotaxy syndrome and single ventricle physiol-

ogy. (15)(16) The incidence of AVSDs ranges from 0.24 to 0.31

per 1,000 live births or 4% to 5% of congenital heart defects

and 40% of cases will be associated with trisomy 21. (16)(17)

AVSD is associated with tetralogy of Fallot in 5% of cases. (16)

DiagnosisA complete AVSD is commonly diagnosed prenatally. (16)

(17) Defects with large ventricular components will present

earlier in life when PVR falls, as discussed earlier. Diagnosis

is made with echocardiography (Fig 3), but ECG can be a

helpful screening test because it commonly shows the

unique finding of a superior QRS axis between –90 and

–120 degrees (Fig 4).

ManagementDefinitive management is surgical, with current mortality

rates less than 3%when performed between 3 and 6months

of age, which increases in younger, smaller infants. (18) The

concurrent diagnosis of trisomy 21 syndrome does not

significantly alter morbidity or mortality rates unless surgi-

cal intervention is made significantly later than 6 months

of age, because of an inherently earlier development of

irreversible pulmonary vascular disease. (16)

PATENT DUCTUS ARTERIOSUS

IncidenceThe PDA is a vital structure in utero, redirecting blood from

the right ventricle to the lower body. After a term gestation,

the PDA will usually close within 72 hours of age, but fre-

quently this does not occur untilmuch later in preterm infants,

making it the most common lesion of prematurity. (19)(20)

DiagnosisPatients may demonstrate a widened pulse pressure with

bounding distal pulses; auscultation of the left upper sternal

border will demonstrate either a continuous murmur

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produced by shunting throughout the cardiac cycle or an

isolated systolic murmur either when the PVR remains

high or as the ductus begins to close and diastolic flow

ceases. As with other left-to-right shunts, echocardiography

is the diagnostic tool of choice. Some investigators have

demonstrated serum brain natriuretic peptide to be another

indicator of PDAs in premature infants. (19)(21)

ManagementSpontaneous PDA closure is more likely to occur in infants

without respiratory distress syndrome, those born after 28

weeks’ gestation (w73%), and those born with birthweights

greater than 1,000 g (w 94%). (19)(22) When closure does

not occur, it is reasonable to consider intervening in the

setting of chronic renal insufficiency, feeding intolerance,

hemodynamic instability, or inability to separate from sup-

plemental respiratory support.Nonsteroidal anti-inflammatory

agents such as indomethacin and ibuprofen are commonly

considered first-line therapy. However, their mechanism of

action (cyclooxygenase inhibition with downstream inhibi-

tion of prostaglandin formation) (23)(24) also carries a sig-

nificant risk of acute renal injury, intracranial hemorrhage,

and spontaneous intestinal perforation. This challenge has

prompted investigation into alternative medical interven-

tions such as intravenous acetaminophen. (24)

Surgical ligation is another option, but is associated with

risks of vocal cordor diaphragmparesis, scoliosis, or accidental

ligation of the pulmonary artery or aorta. (25) Percutaneous

device occlusion is yet another option, but higher rates of

arterial injury and device embolization are reported in infants

who weigh less than 4 kg. (25) Considering the complicated

risk-benefit profile associated with these options, the decision

Figure 3. Apical echocardiogram of an atrioventricular septal defectshowing a primum atrial septal defect (top arrow), a commonatrioventricular valve, and an inlet ventricular septal defect (bottomarrow). LA¼left atrium; LV¼left ventricle; RA¼right atrium; RV¼rightventricle.

Figure 2. Echocardiogram in parasternal long axis view, with and without color, demonstrating a perimembranous ventricular septal defect (indicatedby arrow). LA¼left atrium; RV¼right ventricle; LV¼left ventricle.

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to intervene in an infant with a PDA should not follow a

protocol, but instead be individualized for each patient.

Premature InfantsSome data suggest that the premature ductus arteriosus is

less sensitive to the vasoconstrictive properties of oxygen

and more sensitive to the vasodilatory effects of endogenous

prostaglandin E2, (26) resulting in the higher prevalence

of ductal patency in this population. As with VSDs in the

premature infant, PDAs can be especially challenging be-

cause they contribute to heart failure, bronchopulmonary

dysplasia, necrotizing enterocolitis, renal insufficiency, cere-

bral palsy, and prolonged need for ventilator support. (19)

AORTOPULMONARY WINDOW

Aortopulmonary windows are a rare (0.2%–0.6% of CHD)

systemic to pulmonary communication associated with

severe pulmonary overcirculation, heart failure, and respi-

ratory failure. (27) This defect occurs during embryonic

septation of the truncus arteriosus in which the 2 vessels

have a region devoid of intervening tissue. Without any

interposing resistor such as a semilunar valve or length of

ductus arteriosus, there is no functional separation between

the systemic and pulmonary vascular beds and patients

become symptomatic at very young ages. Physical exami-

nation findings are typically indistinguishable from those of

a large PDA. Echocardiographic diagnosis can be challeng-

ing but should be suspected in patients with a clinical

picture of heart failure without a PDA or VSD. Surgical

patch septation is the definitive intervention.

CONCLUSION

Left-to-right shunting lesions should be physiologically and

anatomically subcategorized into pre- and post-tricuspid

valve. Pre-tricuspid valve lesions include ASDs in which

shunting is determined by defect size and differences in

ventricular compliance. These lesions produce right heart

enlargement and are usually asymptomatic throughout

infancy. Post-tricuspid valve lesions include VSDs, AVSDs,

PDAs, and aortopulmonary windows, in which shunting is

determined largely by the relationship between the systemic

and pulmonary vascular resistances but also by the resistance

inherent in the interposing defect. Initially, these lesions

produce a volume burden on the lungs and left ventricle,

and can lead to progressive respiratory failure, heart failure,

and failure to thrive. Untreated, any of these lesions can

progressively result in Eisenmenger syndrome, which is

associated with a significantly worse prognosis. Premature

infants and those with chronic lung disease are particularly

sensitive to left-to-right shunting lesions and should be

considered for early medical or surgical intervention.

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American Board of PediatricsNeonatal-Perinatal ContentSpecifications• Know the anatomy and pathophysiology (including genetics) ofa neonate with a left-to-right shunt lesion.

• Recognize the clinical features of a neonate with a left-to-rightshunt lesion.

• Recognize the laboratory, imaging, and other diagnostic featuresof a neonate with a left-to-right shunt lesion.

• Formulate a differential diagnosis for a neonate with a left-to-right shunt lesion.

• Know the evaluation and medical and/or surgical managementand associated potential complications or adverse effects ofsuch management for a neonate with a left-to-right shuntlesion.

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13. Minette MS, Sahn DJ. Ventricular septal defects. Circulation.2006;114(20):2190–2197

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15. Hills CB, Kochilas L, Schimmenti LA, Moller JH. Ellis-van Creveldsyndrome and congenital heart defects: presentation of anadditional 32 cases. Pediatr Cardiol. 2011;32(7):977–982

16. Craig B. Atrioventricular septal defect: from fetus to adult. Heart.2006;92(12):1879–1885

17. Morlando M, Bhide A, Familiari A, et al. The association betweenprenatal atrioventricular septal defects and chromosomalabnormalities. Eur J Obstet Gynecol Reprod Biol. 2017;208:31–35

18. St Louis JD, Jodhka U, Jacobs JP, et al. Contemporary outcomes ofcomplete atrioventricular septal defect repair: analysis of the Societyof Thoracic Surgeons Congenital Heart Surgery Database. J ThoracCardiovasc Surg. 2014;148(6):2526–2531

19. Benitz WE; Committee on Fetus and Newborn, American Academyof Pediatrics. Patent ductus arteriosus in preterm infants. Pediatrics.2016;137(1):e20153730

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25. Backes CH, Kennedy KF, Locke M, et al. Transcatheter occlusion ofthe patent ductus arteriosus in 747 infants<6 kg: Insights from theNCDR IMPACT Registry. JACC Cardiovasc Interv. 2017;10(17):1729–1737

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1. A newborn with a murmur undergoes echocardiography and is noted to have an atrialseptal defect (ASD). It is reported that ASDs occur in approximately 1 in 1,500 children andaccount for 6% to 10% of all cardiac anomalies. Which of the following subtypesconstitutes the most common type of ASD?

A. Ostium primum ASD.B. Sinus venosus type ASD.C. Ostium secundum ASD.D. Coronary sinus ASD.E. Mixed ASD.

2. In utero and immediately after birth, the ratio of pulmonary vascular resistance (PVR) tosystemic vascular resistance (SVR) is approximately 1:1. With exposure of the pulmonaryvascular bed to oxygen, the PVR/SVR ratio progressively decreases. When does the PVRnadir occur in a healthy neonate?

A. At 1 week of age.B. Between 2 and 4 weeks of age.C. Between 4 and 8 weeks of age.D. Between 8 weeks and 6 months of age.E. Between 6 months and 12 months of age.

3. A male term newborn is noted at 1 day of age to have a holosystolic murmur.Echocardiography reveals a ventricular septal defect (VSD). VSDs are the most commonform of congenital heart disease, representing 20% to 30% of isolated lesions and occur-ring in 1.3 to 3.9 of 1,000 live births. Which of the following statements is FALSE regardingthe physiology of VSDs?

A. VSDs in the setting of a low PVR/SVR ratio (ie,<0.5:1) produce a pressure burden onboth the lungs and left ventricle.

B. Pulmonary edema is the result of excess pulmonary blood flow with resultantincreased hydrostatic pressures.

C. The classic presentation of a large hemodynamically significant VSD includestachypnea, intolerance of oral feeds, and failure to thrive.

D. If untreated, excess pulmonary blood flow can lead to progressive pulmonaryarteriolar vasoconstriction and irreversible PVR elevation (Eisenmenger syndrome).

E. Due to the lack of flow acceleration and associated murmur, large defects may notbecome clinically evident until an infant becomes symptomatic.

4. A female term newborn has features of trisomy 21 and part of the evaluation includesechocardiography, which reveals an atrioventricular septal defect (AVSD). AVSDs accountfor 4% to 5% of congenital heart defects and 40% of cases are associated with trisomy 21.Which of the following electrocardiographic (ECG) findings is unique to AVSDs?

A. Presence of right ventricular hypertrophy and right axis deviation.B. Presence of a superior QRS axis between –90 and –120 degrees.C. Presence of peaked, large amplitude p waves in lead II.D. Presence of left ventricular hypertrophy with left axis deviation.E. Presence of prolonged PR interval.

5. An infant born at 34 weeks’ gestational age has respiratory distress and is placed oncontinuous positive airway pressure. Chest radiography shows a large cardiac shadow andcardiac murmur. The patient continues to have respiratory distress and oxygenrequirement at 2 days of age and echocardiography is performed. Patent ductus arteriosus(PDA) is present, but otherwise the cardiac anatomy is normal. In full-term infants, the PDAusually closes within 72 hours of age. Which of the following statements is also correctregarding PDAs?

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A. As with ventricular septal defects, shunting occurs exclusively in systole.B. The premature ductus arteriosus is less sensitive to the vasodilatory effects of

endogenous prostaglandin E2.C. The PDA ismore likely to spontaneously close in infants without respiratory distress

syndrome.D. The PDA spontaneously closes in approximately 75% of preterm infants with a

birthweight above 1,000 g.E. The rate of complications associated with percutaneous device occlusion of the

PDA is similar in older children and neonates weighing more than 2,500 g.

Vol. 19 No. 7 JULY 2018 e383 by guest on July 25, 2018http://neoreviews.aappublications.org/Downloaded from

DOI: 10.1542/neo.19-7-e3752018;19;e375NeoReviews 

Jamie N. Colombo and Michael A. McCullochAcyanotic Congenital Heart Disease: Left-to-Right Shunt Lesions

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DOI: 10.1542/neo.19-7-e3752018;19;e375NeoReviews 

Jamie N. Colombo and Michael A. McCullochAcyanotic Congenital Heart Disease: Left-to-Right Shunt Lesions

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