Pathophysiology of left-to-right shunts

INTRODUCTION — In conditions with left-to-right shunt, blood from the systemic arterial circulation mixes with systemic venous blood. Multiple factors influence the extent of flow through the shunt and its physiologic effects.

The pathophysiology of left-to-right shunts is reviewed here. The evaluation and management of specific cardiac lesions are discussed separately, including:

●Atrial level shunts (see "Isolated atrial septal defects (ASDs) in children: Classification, clinical features, and diagnosis" and "Patent foramen ovale" and "Partial anomalous pulmonary venous return" and "Total anomalous pulmonary venous connection" and "Clinical manifestations and diagnosis of atrial septal defects in adults")

●Ventricular level shunts (see "Isolated ventricular septal defects (VSDs) in infants and children: Anatomy, clinical features, and diagnosis" and "Clinical manifestations and diagnosis of ventricular septal defect in adults" and "Tetralogy of Fallot (TOF): Pathophysiology, clinical features, and diagnosis")

●Patent ductus arteriosus (see "Clinical manifestations and diagnosis of patent ductus arteriosus (PDA) in term infants, children, and adults" and "Patent ductus arteriosus (PDA) in preterm infants: Clinical features and diagnosis")

FETAL AND TRANSITIONAL CIRCULATION — In the fetus, oxygenated blood is delivered from the placenta via the umbilical vein, which traverses through the liver via the ductus venosus to join the inferior vena cava (IVC) (figure 1). Approximately 45 percent of the umbilical venous blood enters the portal venous system and perfuses the liver en route to the right atrium, while the remainder enters the right atrium directly. This oxygenated umbilical venous blood, which enters the right atrium from the IVC, is preferentially directed across the patent foramen ovale to the left atrium and ventricle. This provides the coronary circulation and arteries supplying the head and neck with relatively well-oxygenated blood.

Blood returning through the superior vena cava is more likely to cross the tricuspid valve and is ejected via the main pulmonary artery to the lungs or through the ductus arteriosus into the descending aorta. Overall, most of the blood exiting the right ventricle passes right-to-left across the ductus, with only 8 to 10 percent of the fetal cardiac output perfusing the lungs. This distribution of flow is favored by the constriction of the pulmonary arterial bed, resulting in a high pulmonary vascular resistance (PVR), and by the low vascular resistance in the placenta, which results in low systemic vascular resistance (SVR).

With the onset of respiration after delivery, the lungs expand and systemic oxygenation rises. This results in pulmonary vasodilatation and a drop in PVR [1,2]. At the same time, ligation of the umbilical cord removes the placenta from the circulation, with a subsequent increase in SVR. The net impact of these changes is a sudden reversal of blood flow in the ductus from the aorta to the pulmonary artery. In general, increased arterial oxygenation at the ductus results in its constriction and subsequent permanent closure. In addition, the increased pulmonary blood flow, associated with increased pulmonary venous return to the left atrium, usually results in simultaneous functional closure of the foramen ovale. (See "Physiologic transition from intrauterine to extrauterine life".)

As PVR falls, pulmonary artery pressure declines to approximately one-half systemic levels within 24 hours of birth. In the six to eight weeks after birth, PVR continues to decrease as the smooth muscle layer in the pulmonary vasculature becomes thinner. Pulmonary artery pressure becomes close to adult levels during this period.

In the normal infant, following the postnatal period of transitional circulation and closure of the ductus arteriosus and foramen ovale, no communication exists between the systemic arterial (left side) and pulmonary (right side) systems. Systemic venous return is directed to the lungs for oxygenation and returns to the left side to be directed toward the body.

PATHOPHYSIOLOGY — When an abnormal connection exists between the systemic and pulmonary circulations, the potential exists for an excess volume of blood to flow from the systemic (left side) circulation to the pulmonary circulation (right side). These connections include intracardiac defects such as atrial and ventricular septal defects, and vascular connections such as patent ductus arteriosus and arteriovenous fistulae. (See "Clinical manifestations and diagnosis of patent ductus arteriosus (PDA) in term infants, children, and adults" and "Patent ductus arteriosus (PDA) in preterm infants: Clinical features and diagnosis".)

Shunt size — The extent of extra flow is assessed as the ratio of measured pulmonary blood flow (Qp) to systemic blood flow (Qs). In the normal case, where no connection exists, the ratio Qp:Qs is 1:1. Left-to-right shunting results in a Qp:Qs >1, while right-to-left shunting results in a Qp:Qs <1. For example, a Qp:Qs of 2:1 indicates that the pulmonary blood flow is twice that of systemic blood flow.

The overall effect of a left-to-right shunt is the recirculation of already oxygenated pulmonary venous blood through the pulmonary vasculature. This excess pulmonary blood flow results directly or indirectly in almost all of the significant clinical features that characterize heart failure in infants and children.

The pathophysiologic changes that occur depend upon the size of the shunt, which is a measure of the excess volume of pulmonary blood flow [3]. Factors that affect the size of the shunt include the location of the anatomic communication, its size, the age of the patient, and the relative resistances to blood flow on either side of the communication.

Pulmonary effects — Lung mechanics are often abnormal in children with large left-to-right shunts and increased pulmonary blood flow. In one study, for example, tidal volume and lung compliance were lower and expiratory airway resistance was higher in infants with congenital heart disease and left-to-right shunts than in healthy controls [4]. Decreased lung compliance may be exacerbated in patients who also have elevated pulmonary artery pressure.

The mechanism of abnormal pulmonary mechanics is thought to be due to increased extravascular lung water, which appears to be directly related to the increase in Qp. The increased extravascular lung water results from transudation of fluid under increased pressure across capillary walls at rates greater than can be accommodated by lymphatic drainage [5]. If Qp and pulmonary venous pressure are extremely elevated, transudation of fluid into the lungs may result in clinical and radiographic findings of pulmonary edema, although this is uncommon. Pulmonary function abnormalities resolve after surgical repair and normalization of Qp [6].

Neurohumoral activation — The sympathetic nervous system and the renin-angiotensin system are highly activated in patients with left-to-right shunts [7,8]. In one report of children with noncyanotic congenital heart disease, plasma norepinephrine (NE) concentration was higher and lymphocyte beta-adrenergic receptor density was lower in those with than in those without heart failure; epinephrine concentration was similar [7]. The extent of left-to-right shunt flow and pulmonary systolic pressure was directly related to plasma NE concentration and indirectly related to beta-adrenergic density. In another study of infants with left-to-right shunts, NE concentration and plasma renin activity were more closely associated with clinical signs of heart failure, such as tachypnea, than conventional hemodynamic measurements of the volume of shunting, such as Qp:Qs [8].

The cardiac hormone B-type natriuretic peptide (BNP), which has diuretic and vasodilatory properties, is increased in congenital heart disease, as well as in a variety of other cardiac conditions. A study comparing BNP values of a group of patients with congenital heart disease with normal controls showed that patients with a significant left-to-right shunt had increased levels of BNP, with the increase positively correlated with shunt volume [9]. In another study, preterm and full term neonates with significant left-to-right shunts (due to either intracardiac septal defect or patent ductus arteriosus), had higher BNP levels compared with patients who underwent cardiac evaluation but did not have significant left-to-right shunts [10]. (See "Heart failure in children: Etiology, clinical manifestations, and diagnosis", section on 'Laboratory tests'.)

Metabolic effects — Acute and chronic malnutrition are common in children with heart failure, occurring in 60 percent of hospitalized children with left-to-right shunts [11]. The mechanism for poor growth is uncertain but appears to be due to elevated metabolic expenditures associated with increased respiratory effort and myocardial work, leading to decreased nutritional intake and/or increased catabolism. The latter is supported by measurements of increased oxygen consumption in infants with large left-to-right shunts that became normal after surgical correction of the cardiac lesion [12]. In another study, reduced protein or energy intake did not appear to be the primary cause of inadequate growth [13]. (See "Heart failure in children: Management", section on 'Nutritional support'.)

Pulmonary hypertension — The increased pulmonary blood flow caused by left-to-right shunting often is associated with sustained elevation of pulmonary artery pressure, sometimes at systemic levels. This results from failure of the pulmonary microvasculature to undergo remodeling of the pulmonary arteriolar wall that normally occurs in early infancy [14]. Alveolar hypoxia or other local effects that favor pulmonary vasoconstriction may exacerbate this process. In preterm infants with bronchopulmonary dysplasia, atrial level left-to-right shunts are associated with an increased likelihood of pulmonary hypertension [15]. (See "Bronchopulmonary dysplasia (BPD): Clinical features and diagnosis" and "Pulmonary hypertension in children: Classification, evaluation, and diagnosis".)

Initially, there is overgrowth of vascular smooth muscle as well as intimal proliferation, causing gradual effacement of the pulmonary arterioles. These changes lead to loss of the normal reactivity of the pulmonary vascular bed and ultimately result in fixed pulmonary hypertension and irreversible pulmonary vascular disease.

The resulting increased pulmonary vascular resistance may reduce the amount of left-to-right shunting and partly ameliorate signs of heart failure. However, this insidious process ultimately results in permanent injury to the pulmonary vasculature.

Abnormalities of local vascular signaling and impaired endothelial function may be important in vascular remodeling and the development of pulmonary hypertension. This is supported by the demonstration of increased concentration of plasma endothelin, a pulmonary vasoconstrictor [16], and impaired endothelium-dependent pulmonary vascular relaxation [17] in patients with increased pulmonary blood flow due to left-to-right shunts.

CLINICAL MANIFESTATIONS — Patients with increased pulmonary blood flow due to left-to-right shunting can be asymptomatic or have tachypnea or respiratory distress. In general, left-to-right shunts with pulmonary blood flow (Qp):systemic blood flow (Qs) >2:1 have significant hemodynamic consequences.

Typical clinical manifestations of left-to-right shunting include [8,18,19]:

●Tachypnea due to interstitial edema

●Tachycardia and diaphoresis due to increased release of catecholamines

●Poor weight gain resulting from increased caloric demands and myocardial oxygen demands

Affected patients also may develop hepatomegaly.

The clinical manifestations and severity of heart failure were examined in a study of 41 infants (median age 2.5 months) with congenital heart disease who were evaluated by pediatric cardiologists [20]. The most sensitive and specific signs and symptoms of heart failure were a history of poor feeding (<3.5 ounces/feed), tachypnea (respiratory rate >50/min), an audible gallop, and hepatomegaly.

Respiratory effects — Respiratory distress is the most prominent sign of heart failure caused by significant left-to-right shunting in infancy. Decreased pulmonary compliance due to increased interstitial lung water results in increased work of breathing, which is manifested as tachypnea, flaring of the nasal alae, and intercostal retractions. Frank pulmonary edema is uncommon. Excessive pulmonary blood flow may also result in compromise of airways, leading to atelectasis and emphysema. Ventilatory limitations may result in poor feeding. (See 'Pathophysiology' above.)

Pulmonary infections — Children with large left-to-right shunts have increased vulnerability to viral infections that affect the lower respiratory tract, especially respiratory syncytial virus (RSV). In these patients, RSV infection is associated with increased mortality and prolonged hospitalization compared with unaffected children [21]. (See "Respiratory syncytial virus infection: Clinical features and diagnosis in infants and children".)

Poor growth — The increased work of breathing combined with poor intake contributes to poor growth in infants, even when caloric intake appears adequate. Growth may be affected even when the shunt is small and patients are otherwise asymptomatic. In one study, growth significantly improved following repair of isolated secundum atrial septal defect in children with mild failure to thrive [22].

Time of presentation — Because pulmonary vascular resistance (PVR) is elevated, little left-to-right shunting occurs immediately after birth in term newborns, even in those with large communications due to ventricular septal defects or patent ductus arteriosus (PDA). Shunting usually increases as PVR declines during the first postnatal weeks. Clinical manifestations may develop as shunting increases.

Infants tolerate the increased circulating volume poorly compared with older children. This is due in part to their limited capacity to adjust stroke volume in response to increased metabolic demands.

Symptoms may be exacerbated by anemia because oxygen carrying capacity is reduced and cardiac output increases. In contrast, the increased viscosity associated with higher hemoglobin concentration may slightly elevate PVR and decrease shunting [23].

In preterm infants, PVR decreases more rapidly and accelerates the time course for development of left-to-right shunting through a PDA. The resulting excessive flow through the pulmonary circulation frequently causes pulmonary edema, leading to a need for increased ventilatory support and signs of decreased systemic perfusion. (See "Patent ductus arteriosus (PDA) in preterm infants: Clinical features and diagnosis".)

CAUSES OF SHUNTING — Left-to-right shunting can occur due to communications at the atrial, ventricular, and arterial level, which is usually due to a difference in the resistances of each circuit, with blood preferentially shunting from a higher to lower resistance circulation. Shunting at each level results in specific pathophysiologic and clinical effects. The different effects result from differences in the downstream resistance to flow on either side of the communication as well as instantaneous differences in the pressures measured in the chambers on either side of the communication during systole and diastole.

Examples of left-to-right shunts occurring at each level are atrial septal defect (ASD, atrial level), ventricular septal defect (VSD, ventricular level), and patent ductus arteriosus (PDA, level of the great arteries). Shunts frequently occur at more than one level in the same patient. For example, an infant may have ASD and VSD and a PDA.

Other types of left-to-right shunts do not clearly fit into these categories, but their physiologic effects most resemble atrial level shunts. These involve connections between the systemic arterial circulation and a lower resistance system other than the pulmonary vasculature. Examples are hepatic or cerebral arteriovenous malformations and surgically created arteriovenous fistulae.

Atrial level shunts — Lesions at the atrial level that cause left-to-right shunting include ASDs of all types and anomalous pulmonary venous drainage. The principal determinant of shunting at this level is the relative compliance of the right and left ventricles. (See "Isolated atrial septal defects (ASDs) in children: Classification, clinical features, and diagnosis" and "Patent foramen ovale" and "Partial anomalous pulmonary venous return" and "Total anomalous pulmonary venous connection".)

The atria normally fill throughout the cardiac cycle by venous return from the systemic and pulmonary veins and empty into the ventricles through the tricuspid and mitral valves during ventricular diastole. The right ventricle is normally much thinner-walled and more compliant than the thick-walled left ventricle. As a result, blood flows preferentially through the tricuspid valve during diastole. In the presence of an ASD, the more rapid emptying of the right atrium results in left-to-right shunting. The increased pulmonary venous return to the left atrium further favors left-to-right shunting across the atrial communication.

Atrial level shunts often result in enlargement of the right ventricle, which is known as right ventricular volume overload. This finding may be suggested by the electrocardiogram or visualized by echocardiogram. Hormonal measures such as B-type natriuretic peptide may be elevated [24]. However, although pulmonary blood flow (Qp) is increased, it is rare that right ventricular and pulmonary artery pressures are significantly elevated. Exceptions to this occur, such as the concomitant presence of other, more significant intracardiac or vascular lesions that themselves cause increased right ventricular and/or pulmonary artery pressures.

Because left-to-right shunting at the atrial level is primarily dependent upon the diastolic properties of the right ventricle, elevation of systolic right ventricular pressure has little immediate effect on such shunts. However, when elevated right ventricular systolic pressure results in significant hypertrophy of the right ventricle, diastolic compliance may decrease, limiting the volume of shunt.

An exception to the dependence of shunting on relative ventricular compliance is when the ASD is very small. In this case, the size of the defect itself may limit flow. The left-to-right flow in such very small defects is rarely of clinical significance.

Newborns with ASDs may initially have right-to-left shunting. This is due to hypertrophy and decreased diastolic compliance of the right ventricle at birth, resulting from exposure to systemic pressures during fetal development. As pulmonary vascular resistance (PVR) gradually declines postnatally, right ventricular compliance slowly increases and is accompanied by increasing atrial left-to-right shunting. Thus, most infants with ASDs do not present early. An exception is the infant with an ASD who also has obstruction of the mitral valve. In this case, resistance to left ventricular filling is so impaired that blood is forced left-to-right across the defect to fill the right ventricle.

Ventricular level shunts — Ventricular level shunts result from all types of VSDs, including membranous and muscular defects, atrioventricular canal defects, and conoventricular defects. The pathophysiologic changes associated with a VSD depend upon the size of the defect and the resistance to flow distal to the lesion. (See "Isolated ventricular septal defects (VSDs) in infants and children: Anatomy, clinical features, and diagnosis", section on 'Pathophysiology' and "Clinical manifestations and diagnosis of ventricular septal defect in adults" and "Tetralogy of Fallot (TOF): Pathophysiology, clinical features, and diagnosis".)

Consequences of left-to-right shunts at the ventricular level can include:

●Increased Qp – Increased Qp originates from both the left and right ventricles. Left ventricular volume overload may result in hypertrophy and increased end-diastolic pressure, which in turn may cause increased pulmonary venous pressure.

●Pulmonary hypertension – Unrestrictive VSDs often result in significant pulmonary hypertension, with pulmonary arteries facing systemic or near-systemic pressures.

●Metabolic and neurohumoral effects – Recirculation of blood from the left ventricle to the pulmonary circulation occurs at the expense of some systemic blood flow. This may result in the initiation of compensatory reflex mechanisms to maintain organ perfusion, which have deleterious long-term effects.

The size of the defect influences its effect.

Small ventricular septal defects — Small VSDs restrict left-to-right shunting by providing direct resistance to flow. In general, they limit the systolic pressure of the right ventricle to normal or near-normal levels. Their pathophysiologic effects are also minor. They usually result in a small left-to-right shunt, with normal PVR, normal pulmonary artery and right ventricular pressures, and little increase in ventricular stroke work. Symptoms and signs of heart failure are rare.

Moderate ventricular septal defects — In moderate-sized VSDs, some limitation of shunting occurs. However, if PVR is low, a significant left-to-right shunt may develop. This results in volume overload of the left atrium and ventricle and signs and symptoms of heart failure. In these patients, PVR, right ventricular pressures, and pulmonary artery pressures may remain low or be moderately elevated.

Large ventricular septal defects — Large VSDs are unrestrictive (ie, they provide no effective resistance to flow between the right and left ventricles). As a result, pressures in the two ventricles are approximately equal throughout the cardiac cycle, and the overall amount of left-to-right shunt is dependent upon the resistance of the pulmonary and systemic vascular beds.

Associated lesions — Associated stenotic lesions of the right and/or left ventricular outflow tracts modify the flow across a large VSD. For example, tetralogy of Fallot typically includes a large, unrestrictive VSD caused by malalignment of two components of the ventricular septum. However, the amount of left-to-right shunting in this disorder is determined by the degree of obstruction of the right ventricular outflow tract.

Other examples of anatomic obstruction to flow include valvar or supravalvar pulmonic stenosis, hypoplasia of the pulmonary arteries, decreased cross-sectional area of the pulmonary vascular distribution, or pulmonary arteriolar changes. Obstruction to left ventricular outflow, such as subvalvar and valvar aortic stenosis or obstructive lesions of the aortic arch, favor left-to-right shunting. In addition, the physiologic anemia that develops during the first two to three months after birth exacerbates the fall in PVR, increasing left-to-right shunting.

In the presence of large defects, the normal postnatal decline in PVR may be delayed for several months. This reduces the extent of left-to-right shunting and limits the development of left ventricular volume overload and signs and symptoms of heart failure. Thus, newborns with large VSDs may sometimes have a relatively symptom-free ("honeymoon") period before PVR falls. However, as PVR decreases, Qp increases, leading to left atrial and ventricular volume overload. As left ventricular and left atrial pressures rise, pulmonary venous hypertension develops, contributing to pulmonary edema and diminished pulmonary compliance. Paradoxically, the absence of signs of heart failure in an infant with a large VSD may be an ominous sign, as it may suggest the early development of irreversible pulmonary vascular disease. (See "Pulmonary hypertension in children: Classification, evaluation, and diagnosis".)

Changes during cardiac cycle — The degree and direction of shunting through a large VSD varies during the cardiac cycle:

●Left-to-right shunting across the defect mostly occurs during systole and is determined by the relative pulmonary and systemic vascular resistances.

●Shunting is accentuated during the early phase of contraction since the left ventricle is activated before the right ventricle and the left ventricular pressure rises faster than the right ventricular pressure.

●During the early stages of diastole, the left ventricle relaxes more quickly than the right ventricle, resulting in a transient pressure gradient favoring shunting from the right to left ventricle. When PVR is not significantly elevated, blood that is shunted from the right to left ventricle during early diastole flows back into the right ventricle during mid to late diastole as left ventricular diastolic pressure rises. As a result, there is no net ejection of unoxygenated blood into the aorta. However, marked elevation of PVR results in significant right-to-left shunting, with ejection of unoxygenated blood out the aorta and hypoxemia.

●Additional shunting may occur during mid to late diastole due to the slightly higher left ventricular diastolic pressures.

Arterial level shunts — Connections between the aorta and the pulmonary artery include PDA, aorticopulmonary window, aortopulmonary collaterals, and surgically placed aortopulmonary shunts. Similar to a shunt at the ventricular level, the size of a left-to-right shunt at the arterial level depends upon the size of the communication and the relative resistances of the systemic and pulmonary vascular beds. However, in contrast to atrial level shunts, which occur primarily during ventricular diastole, and ventricular level shunts, which occur primarily during ventricular systole, arterial level shunts typically occur throughout the cardiac cycle. This is because the capacitance of the large arteries maintains a pressure during diastole that is greater than the simultaneous pressure in the pulmonary arteries.

Large arterial level communications with significant left-to-right shunting may result in widening of the pulse pressure due to runoff of arterial pressure into the pulmonary arteries. In these cases, systemic blood flow is reduced and diastolic and mean blood pressures are lowered. In addition to engaging reflex mechanisms to preserve organ perfusion as noted above with VSDs, this reduction may disproportionately reduce blood flow to the coronary arteries, which are perfused mainly during ventricular diastole. (See "Clinical manifestations and diagnosis of patent ductus arteriosus (PDA) in term infants, children, and adults".)

OTHER INFLUENCES ON SHUNTING — The extent or direction of shunting is influenced by the presence of other cardiac lesions and/or the development of increased pulmonary vascular resistance (PVR) [3].

Other cardiac lesions — In general, lesions that increase impedance to left ventricular filling or ejection downstream from the anatomic level of a communication favor an increase in intracardiac left-to-right shunting. These include mitral stenosis, left ventricular hypertrophy, stenoses of the aortic valve, and increases in systemic vascular resistance (SVR). SVR may be increased by drugs, disease, or obstruction of a vascular bed (eg, ligation of the umbilical artery at birth).

In contrast, lesions that increase the impedance to right ventricular filling and ejection favor a decrease in left-to-right shunting, and may even result in right-to-left shunting. Such conditions include right ventricular hypertrophy, stenoses of the right ventricular outflow tract and pulmonary arteries, a surgically placed pulmonary artery band, and disorders that result in increased PVR.

Increased pulmonary vascular resistance — PVR may increase in response to excessive pulmonary blood flow, particularly in the face of the high pulmonary arterial and venous pressures often associated with large ventricular and arterial level shunts. Although reflex pulmonary vasoconstriction occurs in response to the high pressures, this protective mechanism is typically superseded over time by pathologic vascular changes. These changes are irreversible and include fibrous and muscular proliferation in the pulmonary microvasculature and gradual obliteration of the pulmonary vascular bed. They are an expected consequence of long-standing, unrepaired left-to-right shunting in adolescents and young adults. The resultant reversal of the shunt to right to left causes cyanosis and is known as Eisenmenger syndrome. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Congenital heart disease'.)

SUMMARY

●Causes – Left-to-right shunting is caused by blood flow through an abnormal connection from the systemic ("left-sided") circulation to the pulmonary ("right-sided") circulation. This results in recirculation of blood through the pulmonary vasculature. (See 'Pathophysiology' above.)

Left-to-right shunting can occur at the atrial, ventricular, or arterial level. Cardiac and vascular defects associated with left-to-right shunting include (see 'Causes of shunting' above):

•Atrial septal defects (see "Isolated atrial septal defects (ASDs) in children: Classification, clinical features, and diagnosis")

•Ventricular septal defects (see "Isolated ventricular septal defects (VSDs) in infants and children: Anatomy, clinical features, and diagnosis")

•Patent ductus arteriosus (see "Clinical manifestations and diagnosis of patent ductus arteriosus (PDA) in term infants, children, and adults")

•Partial anomalous pulmonary venous return (see "Partial anomalous pulmonary venous return")

•Arteriovenous malformations and fistulae (see "Arteriovenous malformations of the extremities")

●Physiologic effects – The physiologic effects of left-to-right shunts depend on the shunt size and can include:

•Abnormal lung mechanics, such as decreased tidal volume and lung compliance, and increased expiratory airway resistance. (See 'Pulmonary effects' above.)

•Activation of the sympathetic nervous system and the renin-angiotensin system. (See 'Neurohumoral activation' above.)

•Elevated metabolic expenditures with increased respiratory effort and myocardial work that results in poor growth because of decreased nutritional intake (poor intake due to fatigue) and increased catabolism. (See 'Metabolic effects' above.)

•Sustained elevation of pulmonary artery pressure, which sometimes reaches the level of systemic pressure. (See 'Pulmonary hypertension' above.)

●Clinical manifestations

•Clinical findings – Typical clinical findings in patients with symptomatic left-to-right shunting include (see 'Clinical manifestations' above):

-Tachypnea

-Tachycardia and diaphoresis

-Poor weight gain

-Recurrent pulmonary infections

-Hepatomegaly (in some patients)

•Timing of presentation – Because pulmonary vascular resistance (PVR) is elevated at birth, little left-to-right shunting occurs immediately after delivery, even with large communications. Shunting typically increases as PVR declines during the first postnatal weeks. Symptoms may develop as shunting increases. (See 'Fetal and transitional circulation' above and 'Time of presentation' above.)