Pathophysiology of Congenital Heart Disease in the Adult
Authors: Robert J. Sommer, Ziyad M. Hijazi, John F. Rhodes
Journal: Circulation (2008)

HomeCirculationVol. 117, No. 8Pathophysiology of Congenital Heart Disease in the Adult Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBPathophysiology of Congenital Heart Disease in the AdultPart I: Shunt Lesions Robert J. Sommer, Ziyad M. Hijazi and John F. RhodesJr Robert J. SommerRobert J. Sommer From the Center for Interventional Vascular Therapy, Cardiovascular Research Foundation, Columbia University Medical Center, New York, NY (R.J.S.); Department of Pediatrics and Medicine, Rush Center for Congenital and Structural Heart Disease, Rush University Medical Center, Chicago, Ill (Z.M.H.); and Department of Pediatrics, Division of Pediatric Cardiology, Duke University Medical Center, Durham, NC (J.F.R.). , Ziyad M. HijaziZiyad M. Hijazi From the Center for Interventional Vascular Therapy, Cardiovascular Research Foundation, Columbia University Medical Center, New York, NY (R.J.S.); Department of Pediatrics and Medicine, Rush Center for Congenital and Structural Heart Disease, Rush University Medical Center, Chicago, Ill (Z.M.H.); and Department of Pediatrics, Division of Pediatric Cardiology, Duke University Medical Center, Durham, NC (J.F.R.). and John F. RhodesJrJohn F. RhodesJr From the Center for Interventional Vascular Therapy, Cardiovascular Research Foundation, Columbia University Medical Center, New York, NY (R.J.S.); Department of Pediatrics and Medicine, Rush Center for Congenital and Structural Heart Disease, Rush University Medical Center, Chicago, Ill (Z.M.H.); and Department of Pediatrics, Division of Pediatric Cardiology, Duke University Medical Center, Durham, NC (J.F.R.). Originally published26 Feb 2008https://doi.org/10.1161/CIRCULATIONAHA.107.714402Circulation. 2008;117:1090–1099Congenital heart disease is common, occurring in ≈8 of 1000 live births.1 With the successes in cardiothoracic surgery over the past 3 decades and the ongoing improvements in the diagnostic, interventional, and critical care skills of pediatric cardiologists, ≈90% of children born with heart defects now survive to adulthood.2 In addition, using improved noninvasive techniques, adult cardiologists are increasingly identifying adults with septal defects that were undiagnosed in childhood. The adult congenital heart disease patients carry a spectrum of disease, from small septal defects and minor valvar obstructions to complex single-ventricle lesions that have been palliated with staged surgical repairs. It is estimated that >1 million adults in the United States now have congenital heart disease, outnumbering their pediatric counterparts for the first time.3,4While the adult cardiology community struggles with a population that once was the exclusive domain of pediatricians, governmental agencies, national physician associations, and cardiology advisory boards are trying to define the scope of this national healthcare issue and to figure out how to train current and future generations of doctors.5 This specialized cardiac care will require the diagnosis of adult congenital heart disease in patients presenting de novo with new or chronic symptoms, the long-term maintenance of those previously diagnosed, and the ability to recognize when primary or additional interventions are required. As these patients increasingly present to cardiologists' offices for care, healthcare professionals will need to develop a better level of comfort with adult congenital heart disease.This 3-part series focuses on the pathophysiology of congenital heart lesions, which are seen commonly in adult patients. In this first portion, simple shunt lesions are reviewed. For each, the natural history and common clinical presentations resulting from the shunt are discussed. A discussion of therapeutic options and the literature supporting these options is beyond the scope of this series. Patient management is limited to a discussion of which patient requires intervention. The second article in the series examines the pathophysiology of simple congenital obstructive lesions; the third looks at the fascinating physiologies of some of the more complex congenital heart malformations.Shunting LesionsPerhaps no aspect of cardiology is as uniquely identified with congenital heart disease as intracardiac shunting lesions. Most adult congenital heart disease patients who require therapy present with a shunt.With normal cardiac anatomy, there is complete septation of oxygenated and deoxygenated blood. The 2 circulations run in parallel, each feeding the other, and maintain a 1-to-1 volume relationship on the systemic and pulmonary sides of the circulation. The deoxygenated, systemic venous return to the right atrium (RA) is pumped to the lungs as the pulmonary blood flow (abbreviated Qp). Once oxygenated, the blood returns via the pulmonary veins to the left atrium (LA) and is pumped to the aorta as the systemic blood flow or cardiac output (Qs). The term "shunt" refers to an abnormal connection allowing blood to flow directly from one side of the cardiac circulation to the other. A left-to-right shunt allows the oxygenated, pulmonary venous blood to return directly to the lungs rather than being pumped to the body. A right-to-left shunt allows the deoxygenated, systemic venous return to bypass the lungs and return to the body without becoming oxygenated. In each case, the circulation is less efficient and creates increased demand on the ventricles. In most patients, the volume of shunted blood determines the severity of symptoms.Left-to-Right ShuntingThe metabolic needs of the body's tissues are highly variable, depending on the patient's level of activity. To maintain normal aerobic respiration at the cellular level, oxygen must be delivered in quantities sufficient to meet those needs. One measure of how well the cellular needs are being supplied is tissue oxygen delivery, the mathematical product of systemic arterial oxygen content and cardiac output.6 By definition, a left-to-right shunt allows a portion of the pulmonary venous return to escape back to the lungs, thereby reducing the cardiac output by the amount of the shunted volume. Tissue oxygen delivery is thereby reduced. The pathophysiology associated with each congenital shunt is reviewed in more detail below.Right-to-Left ShuntingWith normal cardiac anatomy, lung function, and hemoglobin levels, arterial blood oxygen contents vary only to the extent that pulmonary alveolar oxygenation changes. Under most physiological conditions, the blood oxygen content changes little and is more than adequate to supply the needs of the tissues. With a right-to-left shunt, however, deoxygenated systemic venous blood returns directly to the systemic arterial circulation. The oxygen content of the systemic arterial blood falls in proportion to the volume of systemic venous blood mixing with the normal pulmonary venous return. With reduced oxygen content, even with normal cardiac output, tissue oxygen delivery falls and the work capacity of the muscles is limited.6Quantifying Shunt VolumesThe ratio of total pulmonary blood flow to total systemic blood flow, the Qp/Qs ratio, is a useful tool for quantifying the net shunt. A Qp/Qs ratio of 1:1 is normal and usually indicates that there is no shunting. A Qp/Qs ratio of >1:1 indicates that pulmonary flow exceeds systemic flow and defines a net left-to-right shunt. Similarly, a Qp/Qs ratio of <1:1 indicates a net right-to-left shunt. Both left-to-right and right-to-left (bidirectional) shunting may be present in the same patient. If the left-to-right shunt equals the right-to-left shunt in magnitude, it is possible to have a Qp/Qs of exactly 1:1.Atrial Septal DefectThe formation of the atrial septum is a complex process, consisting of the growth and partial reabsorption of 2 tissue membranes, septum primum and septum secundum; the fusion of these membranes to the forming endocardial cushions; and the reabsorption of the fetal sinus venosus into the structure that will ultimately become the RA. In ≈4 of 100 000 newborns,7 an error in this developmental process will result in a defect in the wall separating the 2 atria, an atrial septal defect (ASD). There are a number of types of ASD (Figure 1), including the ostium primum defect (a result of the deficiency of endocardial cushion tissue), the ostium secundum defect (a result of excessive reabsorption of septum primum), and the sinus venosus defect (resulting from an error in the incorporation of the sinus venosus chamber into the RA).8 Although the following discussion of ASD pathophysiology is true for all types of ASD, the sinus venosus ASD also may be associated with anomalous pulmonary venous return and the ostium primum ASD with significant atrioventricular (AV) valve abnormalities. These additional features may complicate the physiology further and are beyond the scope of this review. Download figureDownload PowerPointFigure 1. Types and typical locations of ASDs. In this view, the free walls of the RA and RV have been removed, looking leftward toward the septal surface. MPA indicates main pulmonary artery; 1, sinus venosus ASD at the junction of the superior vena cava (SVC) and RA; 2, ostium secundum ASD; and 3, ostium primum/AV canal type ASD.PathophysiologyThe pathophysiology of an ASD is complex and multifactorial.9 Flow across the defect occurs in both systole and diastole. In most patients, flow is predominantly left to right, but transient right-to-left shunts are common, particularly with isometric strain. The bulk of the shunt flow occurs during diastole. In this phase, blood in each atrium has 2 alternative pathways: following the normal route through the AV valve to the ventricle on that side or passing through the ASD to fill the opposite ventricle. The direction of flow across the ASD during diastole is determined by the instantaneous differences in the compliance and the capacity of the 2 ventricles.Ventricular chamber compliance is determined to a large extent by afterload. (Other factors such as intravascular volume status, myocardial muscle mass, chamber geometry, coronary perfusion, and pericardial and intrathoracic pressures also contribute to the intrinsic distensibility of the chamber.) In an otherwise normal patient, the left ventricle (LV), pumping to the systemic circulation, faces a substantially larger workload than the right ventricle (RV), pumping to the lungs. The LV becomes physiologically hypertrophied, reflecting its level of work, whereas the RV myocardium remains thin. The thick-walled LV will stretch/distend to accept additional volume less readily than the thinner RV. As a result, in the usual ASD patient, the difference in chamber compliance favors a left-to-right shunt because the blood in the LA finds it easier to fill the more compliant RV. In patients with increased RV afterload resulting from congenital obstructions in the pulmonary arteries or veins or with high pulmonary vascular resistance resulting from pulmonary parenchymal disease or primary pulmonary hypertension, the RV will be hypertrophied and less compliant. Left-to-right shunting at the ASD may be minimal, reflecting little overall difference between the 2 ventricles. With more severe RV noncompliance or distensibility, flow across the ASD may be predominantly from right to left. In some patients with reduced RV compliance, the RV may be able to handle a normal cardiac output at rest but will not readily accept additional flow (when cardiac output increases), and a right-to-left shunt may occur only with exertion. Other factors such as a prior RV myocardial infarction, extrinsic compression of the RV, or any associated congenital abnormality that results in RV or tricuspid valve hypoplasia may reduce the effective RV capacity and impede its filling.When the AV valves are closed, ventricular compliance no longer affects blood flow across the defect at the atrial level. Several factors determine flow volume and direction in systole. As in diastole, the size of the defect is a critical determinant in the volume but not the direction of flow. The atria may have differential capacities or compliances themselves, which may affect flow direction during systole. In patients with a large left-to-right shunt in diastole, pulmonary venous return will exceed systemic venous return (because Qp>Qs). Volumes in the 2 atria tend to equilibrate during systole, resulting in a left-to-right flow during that phase of the cardiac cycle. AV valve regurgitation also may affect the direction of ASD flow during systole. Significant mitral or tricuspid regurgitation may impede flow across an ASD, increasing or decreasing shunting during systole.Finally, the size of the ASD itself helps to determine the volume of shunting. If the ASD is large, the defect creates little or no resistance to flow. Blood flow across the defect in diastole is determined entirely by the relative properties of the ventricles as above. With a smaller, restrictive defect, blood flow is limited by the resistance of the ASD itself, no matter how large the difference in ventricular compliance.Natural HistoryIn a patient with an ASD, shunt direction and magnitude are variable and age dependent. In fetal life, RV noncompliance, a result of high pulmonary vascular resistance, allows nearly unidirectional right-to-left flow at the atrial level. Immediately after birth, with RV compliance comparable to that of the LV, there may be little net shunting through an ASD. Over several months, with the physiological fall in pulmonary vascular resistance, the RV thins, compliance falls, and the typical left-to-right shunt develops in children and young adults.As a result of normal physiological changes associated with aging, the LV myocardium tends to become more hypertrophied and less compliant.10 With similarly sized ASDs, therefore, adults tend to have larger shunts as they age. It is part of the reason why children are rarely symptomatic but patients in their fourth or fifth decade may begin to develop the symptoms frequently associated with ASD. There are 4 common clinical presentations of ASD in the adult population.Most frequently, adult patients complain of progressive shortness of breath with exertion. Studies have shown a reduction in maximum oxygen consumption in the unrepaired ASD population because of the inherent inefficiency of a continuously preload-reduced LV in combination with a volume overload in the pulmonary circulation. After repair of the ASD, exercise capacity improves within days to weeks.11,12Atrial arrhythmia, resulting from stretching of the conduction system, may be the first presenting sign of an ASD. An adult who presents with atrial arrhythmia at a young age should be evaluated for dilatation of the right-side cardiac chambers and evidence of an atrial level shunt. Prevention of long-term atrial fibrillation is one of the reasons for repairing ASD in young asymptomatic patients,13 although the subsequent development of atrial fibrillation may depend more on the patient's age at intervention and may occur despite surgery in patients >25 years of age.14 Although both RA and RV volumes are reduced acutely with ASD repair and both chambers return to normal dimensions in children, there appears to be persistent RA enlargement when the ASD is closed in adult patients.15 This may explain an ongoing, increased risk of atrial fibrillation after adult ASD repairs compared with patients who underwent closure at a younger age.16Rarely, a patient with ASD will present with stroke or other systemic ischemic event caused by paradoxical embolization of thrombus through the defect17 similar to the patent foramen ovale (PFO; see below). Although most patients have a significant net left-to-right shunt through the defect, virtually all have transient flow reversal with the Valsalva maneuver or other isometric strain.A small number of adult patients also may be identified echocardiographically when a heart murmur or unrelated cardiac symptoms in the absence of exercise, rhythm, or embolic symptoms bring them to a physician's attention.Pulmonary hypertension is uncommon with ASD, even in patients with large defects, in part because of the large capacitance of the pulmonary bed. Natural history studies dating to the presurgical and pre-echocardiography eras suggested an incidence of ≈15% in the ASD population.18 The observations that pulmonary vascular disease may develop in patients with a tiny ASD and that it is absent in the vast majority of patients with large ASDs suggest that the ASD may be an associated marker of pulmonary hypertension but not necessarily causative. More recent reviews suggest a rate of 6% to 9%.19,20 Once a patient has reached adulthood with normal PA pressures, the natural history is established: They no longer develop significant pulmonary hypertension related to the shunt, but they may have pressure elevation, like any other patient, as a result of the development of pulmonary parenchymal disease, left-sided heart dysfunction, or obstructive sleep apnea. It would be fair to say that the overall risk of and specific risk factors for developing pulmonary vascular disease with an ASD remain unknown.When severe pulmonary hypertension from any cause results in RV systolic failure, high RV end-systolic volumes impede filling from the RA. With an intact atrial septum, there is systemic venous stasis and symptoms of "classic" right-heart congestive failure (anasarca and low cardiac output) because the LV can pump out only what it receives back from the lungs. In a patient with pulmonary hypertension and an ASD, however, the defect allows decompression of the right heart via a right-to-left shunt. The systemic venous blood does not need to traverse the lungs to reach the LV. It may cross through the ASD, mixing with the pulmonary venous return in the LA, to augment LV preload. These patients are cyanosed from the right-to-left shunt and show minimal response to supplemental oxygen.21 However, tissue oxygen delivery is often better than in the patient without an ASD because the detrimental reduction in blood oxygen content is far outweighed by the maintenance of a normal or nearly normal cardiac output. For this reason, it is likely that repair of adult patients with ASD and moderate or severe pulmonary hypertension may not improve survival.16 Similarly, in patients with end-stage primary pulmonary hypertension, the creation of an ASD has been demonstrated to be of benefit in prolonging life and as a bridge to lung transplantation.22Indications for InterventionSignificant questions remain about which ASDs should be closed because the natural history of the disease remains elusive. Generally accepted indications for closure of ASD include patients with ASD and echocardiographic evidence of right-sided cardiac volume loading, patients with ASD who are symptomatic (principally exercise related), patients with ASD with exercise-related cyanosis (without pulmonary hypertension), patients with ASD who have suffered an episode of paradoxical thromboembolization, and potentially as prophylaxis in patients who require a noncardiac procedure with high risk of paradoxical embolization (ie, joint replacement therapy). A traditional open heart approach, dating back to 1954,23 and newer minimally invasive and robotic techniques24 are all available for surgical repair of the defects. The success and safety of transcatheter techniques have significantly increased the number of percutaneous closure procedures.25,26As above, pulmonary hypertension, with right-to-left shunting at rest (or a pulmonary vascular resistance of >14 Woods units), is the principal contraindication to ASD closure.20 However, patients may present with intermediate degrees of pulmonary hypertension with bidirectional or predominantly left-to-right shunts. It may be difficult with the limited data available in the literature to decide which of these patients should be offered closure. We have used temporary balloon occlusion of the ASD in the catheterization laboratory as our primary determinant. With occlusion of the defect and elimination of the right-to-left shunt, one can directly assess the acute impact on RA and pulmonary artery pressures and on cardiac output.Similarly, patients may present with signs of left-sided congestive heart failure with a left-to-right shunt at the atrial level. Typically occurring in the elderly, this is related to changes in LV compliance (ie, status after myocardial infarction). In this scenario, the stiffer the LV chamber becomes, the larger the left-to-right shunt is. The shunt acts as a "popoff" for the LA, allowing the patient to maintain manageable pulmonary venous pressures, but also reduces LV preload and cardiac output. With closure of such a defect, the full impact of the LV diastolic dysfunction is felt (because all pulmonary venous return is forced into the LV), resulting in an acute rise in LA pressure and the potential development of pulmonary edema. Temporary balloon occlusion in the catheterization laboratory, with simultaneous LA pressure measurement, can be used to decide which patient will tolerate ASD closure.Patent Foramen OvalePFO, another communication in the atrial septum, is a remnant of the normal fetal circulation. Anatomically, the foramen ovale comprises overlapping portions of septum primum and septum secundum, acting as a 1-way flap valve allowing continuous right-to-left flow during fetal life. Because all venous blood (both deoxygenated systemic and the high-oxygen umbilical venous return) drains to the RA throughout fetal life, right-to-left flow is critical for perfusion and growth of the left heart. Postnatally, septum primum fuses to septum secundum, completing septation of the atria.8 However, in 20% to 25%, incomplete fusion leads to the persistence of the flap valve, leaving a PFO. Because it is present in all newborns, a PFO technically is not a "congenital" defect. But as the most common "hole in the heart" and currently the most common catheter intervention for structural heart defects,27 the PFO is deserving of mention in this discussion.PathophysiologyImmediately after birth, with the acute increase in pulmonary blood flow, LA pressure rises to exceed RA pressure, pushing septum primum rightward, against septum secundum, shutting the flap of the PFO. When RA pressure rises intermittently with Valsalva or other isometric strain, the leaflets of the PFO may separate, with leftward excursion of septum primum, allowing flow from RA to LA, as was the norm throughout fetal life.The degree to which the leaflets separate, the frequency with which the flap valve opens, and the amount of blood that crosses from right to left depend on a number of variables, including RV compliance, the difference in RA and LA pressure, distortion of the anatomy (ie, dilated aortic root, elevation of right hemidiaphragm), and most important, the tissue characteristics of septum primum. With a relatively rigid septum primum, right-to-left flow may occur only with strain. At the other extreme, the septum primum may be extremely thin and mobile, the so-called atrial septal aneurysm, and may open spontaneously with the changing phases of the cardiac or respiratory cycle. If septum secundum is less sturdy or in the case of LA hypertension, septum secundum may be pushed rightward and left-to-right shunting can be seen, the functional equivalent of a prolapsing or regurgitant valve. It is common for such a PFO to be labeled an ASD, although with clear overlap of septum primum and septum secundum, it is preferentially called a PFO.Natural HistoryIn general, patients with PFO are never identified because they have no symptoms. Paradoxical embolization of thrombotic material is the most frequent clinical presentation.28 Although thromboembolic events to noncritical systemic structures may go unnoticed, cerebral embolization may produce stroke or transient ischemic attack,29 and coronary embolization may result in myocardial infarction in the absence of atherosclerotic disease.30 Splenic, hepatic, renal, and retinal infarcts have all been seen in our practice in patients with no risk factors other than PFO. Therefore, when no other source of thromboembolism can be detected, a PFO may be suspected.31A number of other clinical syndromes are being studied for their apparent relationship to PFO, including migraine headache,32,33 hypoxemia,34 and decompression illness in divers and in people who work at altitude,35 as well as high-altitude pulmonary edema.36 The mechanism of the migraine relationship to PFO remains entirely unknown. Hypoxemia may occur in a patient with PFO, like in ASD, when RV compliance or capacitance is diminished and hemodynamics favor a right-to-left flow across the PFO. This physiology has been described for patients with obstructive sleep apnea,37 after pulmonary embolic events,38 and with RV infarction.39 In addition, significant hypoxemia can occur in the presence of normal right-heart pressures when anatomic distortion of the atrial septum accentuates right-to-left shunt at the atrial level, the platypnea orthodeoxia syndrome.40 These patients experience an acute fall in arterial oxygen saturation on changing from a supine to an upright position. Decompression illness is presumed secondary to right-to-left air embolization through the PFO in divers or people who work at altitude.35Indication for InterventionDespite the rapid growth, relative ease, safety, and efficacy of transcatheter devices,41–44 particularly compared with surgical closure, there are currently no approved indications for transcatheter PFO closure in the United States. Each patient with PFO should be considered individually. Treatment depends on the presenting symptom. Because the vast majority of patients with isolated PFO never have symptoms, there is no rationale for prophylactic closure in asymptomatic patients at this time.For patients who have had paradoxical embolization, treatment options include antithrombotic agents, entrance in a randomized trial comparing blood thinners and closure, "off-label" transcatheter closure with a non-PFO device, or surgical repair. Because prospective, randomized, controlled trials are not yet completed, there is no definitive answer as to which therapy provides the best long-term prophylaxis from recurrent stroke. Similarly, there are few prospective data to date to support the closure of PFO in migraine sufferers. Multiple studies addressing this question are underway in the United States and Europe.In contrast, patients with the platypnea orthodeoxia syndrome should have their PFO closed in all cases. Closure results in immediate elimination of right-to-left shunting and normalization of oxygen saturation. Recurrent decompression illness in divers may be preventable with PFO closure, although few data exist at this point.Ventricular Septal DefectVentricular septal defect (VSD) is the most common form of congenital heart defect in children, accounting for ≈20% of human cardiac malformations. This is undoubtedly based on the complexity of the embryological development of the ventricular septum, which involves the fusion of multiple distinct septal components.45 The membranous septum, the site at which all of these components fuse, sits behind the septal leaflet of the tricuspid valve and immediately below the aortic valve in the LV outflow tract. The perimembranous type of VSD, which accounts for ≈80% of all VSDs, occurs in this location. Defects of the muscular septum are the next most frequent, are the result of excessive fetal muscular resorption, can be single or multiple, and can be located anywhere in the muscular septum. Endocardial-cushion–type VSDs (associated frequently with primum ASD as part of a complete AV canal defect), malalignment defects, and other defects of the outlet septum are less common (Figure 2). Endocardial-cushion VSDs often are associated with AV valve insufficiency, and outflow defects often are associated with aortic insufficiency, which further complicate the physiological consequences of the lesion. Download figureDownload PowerPointFigure 2. Types and typical locations of VSDs. In this view, the free walls of the RA and RV have been removed, looking leftward toward the septal surface. SVC indicates superior vena cava; 1, perimembranous VSD; 2, muscular VSD; 3, inlet/AV canal type VSD; and 4, subpulmonary VSD.PathophysiologyThe hemodynamic effects of a VSD are very different than those of an ASD. With a VSD, blood in each ventricle has 2 possible systolic pathways: through the usual outflow tract of that ventricle or through the VSD to the outflow tract of the other ventricle. It is the comparative resistance of each pathway that determines both the direction and volume of systolic flow across the VSD according to Ohm's law.45 For example, with normal pulmonary vascular resistance and a large, nonrestrictive VSD, the sum of resistors from the LV to the pulmonary artery is very low compared with the resistance of flow to the systemic circulation, resulting in a large left-to-right systolic flow across the defect. If the VSD is very small, there is high resistance at the defect itself, limiting the left-to-right shunt, even with low pulmonary resistance. With elevation of pulmonary vascular resistance and a large defect, the sum of the resistors may approximate the aortic resistance, and net shunting will be minimal. With pulmonary resistance higher than systemic resistance, the shunt will be right to left, no matter what size the defect is.A left-to-right shunt at the ventricular level reduces LV output by the amount of the shunt. However, the body's compensatory mechanisms will increase intravascular volume in