Coarctation of the aorta

J. Arab Neonatal Forum 2006; 3:5-13

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Coarctation of the Aorta: A Comprehensive Review Mohamed A Hamdan

Department of Paediatrics, Tawam Hospital, Al Ain, United Arab Emirates __________________________________________________________________________________________ Abstract Coarctation of the aorta (COA) causes obstruction in the descending aorta (DAO), but has a heterogeneous spectrum of clinical presentation. There is increasing evidence of genetic influence to explain its occurrence in family members and association with other left heart obstruction (LHO) lesions. Several treatment modalities are available including trans-catheter interventional procedures, but long-term morbidity related to hypertension remains substantial. Key words: Coarctation of aorta, fetal echocardiography, genetics, paediatrics COA was first described by Morgagni in 1760 as a zone of constriction in the DAO.1 COA accounts for 5-7% of congenital heart disease (CHD), with an incidence of 0.3-0.4/1000 live births.2,3,4 In necropsy studies, COA is found in 6% of fetuses, 43% of which have chromosomal anomalies, particularly monosmoy X.5 Similar to other forms of LHO lesions, there is a slight male preponderance. Natural history studies showed that the median age of death for unrepaired COA was 31 years.6 Death was attributed to cardiac failure in 26% of patients, while aortic rupture, infective endocarditis, and inracranial haemorrhage occurred in 21%, 18%, and 12% of patients, respectively.6

Aetiology Coarctation is a narrowing in the DAO, at the insertion site of the ductus arteriosus (DA), adjacent to the origin of the left subclavian artery (LSCA), 'juxtaductal' coarctation (Fig. 1). However, obstruction could also occur in the transverse aortic arch, or abdominal aorta. It can be discrete or tubular, and is associated with various cardiac and non-cardiac abnormalities in up to 50 % of patients.7,8,9 (Table 1).

Although it results from abnormalities in the development of the embryonic fourth and sixth aortic arches, COA is quite diverse in severity and presentation. The underlying mechanisms are not fully understood, but two concepts have been proposed: the ductal tissue theory, and reduced-flow theory.

Ductal tissue theory Tissue from the DA invades the DAO just distal to the aortic isthmus. When the DA constricts, coarctation occurs. This is supported by the fact that neonatal coarctation manifests only after ductal closure, ('infantile' type), and usually has more severe symptoms. The obstruction appears as an _____________________________ Contact Address: Dr. Mohamed A. Hamdan Department of Pediatrics, Tawam Hospital, P.O. Box 15258, Al Ain, UAE Tel.: (+971) 3707 2181 Fax: (+971) 3707 2731 Email: [email protected]

Figure 1: Echocardiogram of an 8 day-old neonate with critical coarctation of the aorta (yellow asterisk) after commencing prostaglandin E1 infusion. There is large patent ductus arteriosus (white asterisk) alleviating the obstruction adjacent to the origin of the left subclavian artery (LSCA). The ‘posterior shelf’ contributing to the obstruction is seen (small arrows). AAO: ascending aorta Table 1: Prevalence of associated lesions

Lesion Prevalence Bicuspid aortic valve 50% Ventricular septal defect 30% Transverse arch hypoplasia 30% Aortic stenosis 15% Mitral valve abnormalities 10% Complex congenital heart disease

6%

Berry aneurysm in the circle of Willis

5%

Extracardiac anomalies 28% Chromosomal anomalies 40%

Adapted from Kiraley et al.7, Beekman et al.8, and Paladini et al.9

indentation (posterior shelf) in the postero-lateral side of thoracic descending aorta (DAO) opposite to the insertion site of the DA.8,10 (Fig. 1). This theory however, fails to explain the occurrence of coarctation in several other sites. Reduced-flow theory Under this concept, defects can develop secondary to haemodynamic disturbances that reduce flow to the

Coarctation of the Aorta

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Table 2: Presentation of coarctation

Fetus -ventricular disproportion -great vessel disproportion -associated with other congenital heart disease -nuchal thickening/ -chromosomal abnormality

(Turner’s syndrome) Neonate

-collapse, acidosis -heart failure -systolic/continuous murmur conducted to back -weak or absent femoral pulses -upper limb hypertension

Infant -heart failure -systolic/continuous murmur conducted to back -weak or absent femoral pulses -upper limb hypertension -cardiomyopathy rarely

Child, adolescent, and adult -systolic/continuous murmur conducted to back (collateral murmurs over scapula rarely) -weak or absent femoral pulses (radio-femoral delay in older patients) -upper limb hypertension -exercise intolerance, leg fatigue and claudication, or cold feet -cardiac arrest (left ventricular hypertrophy and arrhythmia) -hypertensive retinopathy -aortic dissection/ rupture -intracranial bleed -infective endocarditis

(Reproduced with permission from: Coarctation of the aorta from fetus to adult: curable condition or life long disease process? Rosenthal E. Heart 2005;91:1495-1502,) affected sites. In the normal fetus, the left ventricle (LV) ejects 30% of the combined ventricular output, but the aortic isthmus (proximal DAO between LSCA and patent DA) receives only 10%, resulting in a much smaller diameter than the DAO. If the LV flow is further reduced, further narrowing of the isthmus occurs, and coarctation develops (Fig. 2). This explains the common association between the different types of LHO lesions.8,10 The work by Fishman and colleagues supports this hypothesis.11

Lamb models of hypoplastic left heart syndrome (HLHS) and congenital aortic stenosis were created by altering the pre- and afterload conditions of the LV.11 Normal preload resulted in normal LV growth, but banding the ascending aorta resulted in hypoplastic stenotic aortic valve, and extremely-thick diminutive LV.11 Recently, Loscalzo et al showed an

association between fetal lymphoedema and COA in patients with Turner syndrome, where jugular lymphatic obstruction in fetal life compresses and reduces flow to the ascending aorta, resulting in several LHO lesions, including COA, bicuspid aortic valve, and HLHS.12

Role of Genetics It is now well-known that cardiovascular morphogenesis is controlled by numerous genes and trasnscription factors.13,14 Animal models of CHD were developed in transgenic and knockout mice. For LHO lesions, although no specific candidate gene(s) have yet been identified, there is evidence of ‘left heart obstruction gene(s)’ to explain the association between the different types of LHO lesions among family members. First-degree relatives of patients with LHO have increased incidence of other LHO lesions, especially bicuspid aortic valve.15 The recurrence risk in the offspring of patients with LHO is 7-13% which is higher than other types of CHD.16

Levy et al found that 14% of the offspring of mothers with phenylketonuria have CHD, compared to 1% for the control group.17 LHO lesions accounted for the majority of the defects including COA (20%), HLHS (11%), and aortic and mitral valve problems (12% and 6% respectively). This is thought to result from specific mutations in the phenylalanine hydroxylase gene.17

Patients with Turner syndrome provide another evidence of genetic influence. CHD occurs in up to 71% of patients with Turner syndrome, mostly LHO including COA (14%), bicuspid aortic valve (12%), and HLHS (1.2%).18,19,20 Whether this is caused by haploinsufficiency for X-chromosome gene(s) involved in cardiovascular development, or secondary to fetal lymphoedema (webbed neck) interfering with cardiac and vessel formation is unclear.12,19 Boucher et al however, provide evidence that fetal lymphoedema in patients with Turner syndrome, may indeed be related to a critical region for lymphoedema gene located at Xp11.4.21

Finally, Andelfinger et al described a family with dysmorphic features and renal anomalies, associated with bicuspid aortic valve, and COA.22 Linkage analysis showed a mutation in the gene KCNJ2 encoding for inward-rectifying potassium channel Kir2.1.22

Pathophysiology The haemodyanamic effects of COA vary, and depend on the severity of the obstruction, associated cardiac lesions, and compensatory mechanisms. In the fetus, minimal haemodyanamic disturbance occurs because only 10% of the combined ventricular output passes through the isthmus. However, after birth, ductal closure leads to various disturbances ranging from mild systemic hypertension, to congestive heart failure, and shock. Aortic obstruction impedes LV output, causing significant


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pressure overload, and elevated LV end-diastolic pressure. In neonates, the pressure load happens acutely with the onset of ductal closure, resulting in myocardial dilation, and symptoms of congestive heart failure. With severe obstruction, myocardial dysfunction, reduced stroke volume, and cardiogenic shock develop. Compensatory mechanisms aiming at augmenting cardiac output are activated including the Frank-Starling mechanism, the renin-angiotesin, and the sympathetic systems.8 However, these mechanisms may not be effective in the immature neonatal myocardium, because of decreased ß-adrenergic receptor innervation, and decreased LV compliance compared to the adult myocardium.8,10 With chronic or gradual obstruction, other compensatory mechanisms are activated including LV hypertrophy.

Several vascular abnormalities develop in patients with COA in the vessels proximal and distal to the obstruction.23 Neonates and children with COA have reduced distensibility, and increased reactivity to norepinephrine in the vessels proximal to the coarctation site.24,25,26 Plasma renin activity increases substantially, and baroreceptor reflexes are reset to a higher blood pressure (BP).27,28 These abnormalities can persist long after surgical repair, and contribute to the development of systemic hypertension, and premature coronary and cerebrovascular death.

Clinical Presentation The spectrum of clinical manifestations of COA is variable, and depends on the degree of obstruction, and associated lesions. Table 2 summarizes the clinical manifestations in different age groups.3

Neonates and infants The presence of weak femoral pulses, and upper-to-lower extremity difference of BP, correctly identifies neonates with COA.29,30 Crossland et al showed that an isolated upper-to-lower extremity BP difference of >20 mmHg has a sensitivity rate of 92%.30 An important differential diagnosis of shock in the neonatal period is LHO, including COA. Unfortunately, in infants below 6 months of age with COA and cardiac failure, the diagnosis can be mistaken for sepsis or pulmonary disease in almost half.29

Children and adolescents Although older children and adolescents present with more classical signs of COA (Table 2), Ing et al showed that only 4% of children over 1 year of age were correctly diagnosed with COA prior to cardiology referral, despite having abnormal femoral pulses, or upper-extremity hypertension in the majority of them.31

Physical Examination In infants with cardiogenic shock, murmurs can be absent, secondary to poor cardiac output, and minimal flow across the coarctation site. Once prostaglandin E1 (PGE1) infusion is commenced, a

soft systolic ejection murmur or continuous murmur radiating to the back can be appreciated (Table 1). Signs of congestive heart failure and poor perfusion are present. In older children, a systolic ejection murmur radiating to the back, or continuous murmur, represent the most common cause of referral for cardiac evaluation.31

Diagnosis Antenatal diagnosis Fetal echocardiography can correctly identify COA in 30-71% of cases.9,32,33 Asymmetry of the size of the great vessels or ventricles, and narrowing of the aortic arch may provide a clue to diagnosis(Fig. 3).3,32 Antenatal diagnosis improves survival, and perioperative clinical outcome. In a comparative study, infants with postnatal diagnosis of COA had significant increase in the perioperative morbidity and mortality, secondary to ventricular dysfunction, and end-organ failure.34

Chest roentgenogram Neonates presenting in cardiac failure or shock, have cardiomegaly and pulmonary oedema, which is not specific for COA. Older children and adolescents can develop mild cardiomegaly secondary to LV hypertrophy. A "figure-of- 3" sign on the frontal film may be seen because of localized indentation at the coarctation site, associated with prominent arch proximally and DAO distally. Rib notching is commonly seen after 5 years of age. It results from erosions in the inferior edge of the ribs secondary to tortuous pulsating intercostal arteries.

Electrocardiography Infants with COA may have normal electrocardiogram. However, with heart failure and shock, right or combined ventricular hypertrophy develops, together with a 'strain' pattern of ST-segment and T-wave depression indicating subendocardial or myocardial ischaemia (Fig. 4). In older children, LV hypertrophy can be seen with prolonged obstruction. Echocardiography The cornerstone of diagnosis remains echocardiography. Two-dimensional echocardio-graphy can establish the diagnosis, and delineate the site of obstruction and associated lesions (Fig. 1). Flow and colour Doppler measure the peak pressure gradient across the obstruction (Fig. 5). LV dimensions and function are assessed by M-mode. Magnetic Resonance Imaging (MRI) Recent advances in MRI technology enabled its use in patients with COA to provide high-quality two- and three-dimensional images. MRI can define the exact location and severity of COA, the anatomy of the aortic arch, and presence of collateral flow (Fig. 6). Measurements using cardiac MRI correlate well with cardiac catheterization gradient and identify patients who require transcatheter or surgical treatment.35


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Figure 2: Diagram of normal fetal circulation. (A) Superior vena cava (SVC) blood flow (blue arrow) is directed through the tricuspid valve to the pulmonary artery via the arterial duct to the lower body segment. Inferior vena cava (IVC) blood flow (red arrow) containing oxygenated blood from the placenta is directed across the foramen ovale to the left ventricle, ascending aorta and upper body segment with little flow across the isthmus, between the left subclavian artery and the arterial duct. (B) Coarctation of the aorta in utero does not affect the fetal blood flow pattern. (C) After birth there is a fall in pulmonary resistance and increased pulmonary blood flow (blue arrows) and forward flow from the aortic arch to the descending aorta (red arrow). (D) As the ductus constricts, the narrowing of the coarctation is accentuated and the increasing obstruction leads to a gradient (red dotted line). (Reproduced with permission from: Coarctation of the aorta from fetus to adult: curable condition or life long disease process? Rosenthal E. Heart 2005;91:1495-1502).

Figure 3: Fetal echocardiogram showing hypoplastic transverse aortic arch (white asterisk), and coarctation of the aorta (yellow asterisk). AAO: ascending aorta, DAO: descending aorta. Cardiac Catheterization Non-invasive diagnostic tools (such as echocardiography, and cardiac MRI) have mostly replaced cardiac catheterization as a mode of diagnosis. The main role of cardiac catheterization

Figure 4: An electrocardiogram of a 10 day-old neonate with critical coarctation of the aorta, who presented in cardiogenic shock. There is tall R in V1 and deep S in lead I, indicating right ventricular hypertrophy. The strain pattern is evidenced by ST-segment depression and T-wave abnormalities seen in several leads (asterisks). Peaked P-waves in lead II indicates right atrial enlargement.

Figure 5: Color Doppler echocardiogram of discrete coarctation of the aorta (COA), showing mosaic color turbulence across the obstruction. AAO: ascending aorta, DAO: descending aorta.

now is transcatheter treatment. Occasionally, further information may be requested in neonates and infants in the presence of associated lesions or arch hypoplasia, prior to surgical treatment. Treatment of coarctation is indicated when the obstruction gradient during cardiac catheterization is > 20-30 mmHg.36,37

Management When fetal diagnosis of COA is made or suspected, delivery should be planned at a centre where cardiac care services are available. After delivery, once the diagnosis is confirmed, the neonate is either watched carefully, or infusion of PGE1 is initiated until repair is accomplished. In neonates with borderline obstruction, regular assessment of femoral pulses and four-limb BP should be done, until it is clear whether coarctation is present or not.3 Once obstruction is excluded based on clinical examination, and after the ductus closes, these neonates can be discharged home, to be reviewed at regular intervals up to six months of age, as late presentation of coarctation is possible.32 Infusion with PGE1 should be initiated promptly in neonates who develop cardiac failure or shock. These patents often require mechanical ventilation, correction of acidosis, and judcious use


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Table 3: Complications of treatment

Surgery -residual obstruction -bleeding, haemothorax, chylothorax -recurrent laryngeal nerve/ phrenic nerve palsy -Horner’s syndrome -paradoxical hypertension -paraplegia -restricted arm growth -vertebro-basilar steal -cerebral ischaemia -aneurysm -scoliosis -complications of cardiopulmonary bypass

Transcatheter treatment

-residual obstruction -paradoxical hypertension -femoral artery damage -bleeding -aortic dissection/ rupture/ aneurysm -balloon rupture/ embolus -stent migration/ malposition

of inotropic agents. PGE1 dilates the ductus and minimizes the obstruction in 80% of neonates up to 28 days of age, within a mean of 3 hours (Fig. 1).38,39 Lack of response to PGE1 could either be secondary to complete anatomical closure, or irreversible functional closure resulting from lack of receptor sensitivity to PGE1.38 Effective dose of PGE1 varies between 0.002-0.1 µg/kg/min, and it is unclear whether ductal dilation is dose-dependant. Early observations suggest that age >28 days, and weight <4 kg, are associated with PGE1 failure.38 Lewis at al reviewed the side effects in 492 infants treated with PGE1 for various types of CHD.40 Major side effects occurred in 12-16% of infants and were related to low birth weight (<2 kg), prolonged use (>48 hours), arterial infusion, and high dose (> 0.1 µg/kg/min). The most common side effects observed were: respiratory depression (11%), cutaneous vasodilation (7%), rhythm disturbances (7%), seizures (7%), and hyperthermia (4.5%).40

Once the patient’s haemodynamic condition stabilizes, definitive treatment is undertaken. Surgery Surgical repair of COA is the oldest treatment modality, described more than 50 years ago.41

Surgical options include resection of the narrow segment with end-to-end anastomosis, patching with the LSCA or synthetic patch, or placement of a 'jump'

graft. Among the different techniques, end-to-end anastomosis is the most-widely used approach, especially in neonates, and has the best long-term results.42,43,44 LSCA-flap aortoplasty results in collateral flow to the left upper extremity, resulting in restricted arm growth, or blood 'steal' from the left vertebro-basilar artery (Table 3). When synthetic materials are used, there is risk of aneurysm formation at the site of repair.43 Repair is usually performed via left lateral thoracotomy without cardiopulmonary bypass. However, median sternotomy provides better exposure in the presence of associated cardiac lesions (such as ventricular septal defect) or with extensive arch reconstruction. During repair, the proximal transverse arch is clamped, resulting in controlled ischaemia of the distal carotid and vertebral arteries. Blood supply to the left brain is maintained through the contralateral vessels proximal to the clamped site. Although this is generally well tolerated, Azakie et al have recently shown that oxygen supply to the left cerebral hemisphere is impaired during arch clamping.45 The long-term significance of this finding is unclear. Perioperative mortality for repair of isolated COA is low and ranges from 0-8.5%, but higher mortality occurs in neonates and infants in the presence of preoperative cardiac failure or shock.42,43,46-50

The most common complication after surgery is recurrent coarctation and residual hypertension, occurring in 3-4% and, 25-38% of patients, respectively (Table 3).44,50-53

Transcatheter Treatment Interventional treatment of COA has become an accepted alternative to surgery. It has an excellent safety profile, and at least comparable results to surgery, especially in re-coarctation.

Figure 6: Magnetic resonance imaging of an adult with discrete COA just distal to the takeoff of left subclavian artery (black arrow). There are numerous large collaterals present (white arrows). AA: ascending aorta, COA: coarctation of the aorta, DA: descending aorta, ITA: internal thoracic arteries, LA: left atrium, LV: left ventricle. (Reproduced with permission from: Aortic Coarctation and Bicuspid Aortic. Bruce CJ, Breen JF. N Engl J Med 2000;342:249).


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Figure 7: Antero-posterior aortogram in a 7 month-old infant with (A) discrete coarctation of the aorta (arrow). (B) balloon angioplasty. (Courtesy of Dr. Michael Slack, Children’s National Medical Center, Washington, DC, USA). Balloon angioplasty (BA)

Lock et al performed the first balloon angioplasty in excised segments of human COA.54 Since then, BA became a standard method of treatment in both native and recurrent COA.37,55,56 BA produces a tear in the thickened intima and media of the narrow aortic segment, dilating the obstruction (Fig. 7). However, this could extend into the healthy adjacent aorta causing rupture, or aneurysms.54,55,57 BA is generally avoided in the first 6-12 months of life in patients with native COA, because of high risk of re-coarctation (57%), aneurysm formation (17%), and femoral artery damage (39%).58,59 In post-operative coarctation however, BA can be successful in up to 91% of infants, and is advocated as alternative to surgery.37 Although it may have higher risk of aneurysm and femoral artery injury than surgery, many centres use BA as a primary treatment for COA beyond infancy, with excellent long-term results.57,60

Stent placement Balloon-expandable stents have been used successfully since the early 1990’s, to relieve the obstruction in animal models, and humans with COA.36,61,62,63 Stents support the integrity of the vessel wall during balloon dilation and create a more-controlled tear. This minimizes tear extension and subsequent dissection or aneurysm formation. Aneurysms occur in 4-7% after either BA or stent placement for COA.55,56,62,63 Despite the initial reports of stent placement in neonatal and infantile COA, the long-term results were disappointing.62,63 Stents implanted at a young age are limited by their small sizes to accommodate somatic growth. They are therefore reserved for adolescents and adults as a primary treatment.36 Long-term follow-up of stent implantation in COA is currently lacking. Table 3 lists complications of surgical and transcatheter treatment.

Prognosis Despite excellent results overall for surgical and transcatheter treatment in patients with COA, long-term morbidity and mortality remain substantial. Cohen et al reviewed the Mayo Clinic experience of 571 patients operated between 1946 to 1981.50 At a median follow-up of 20 years, 11% of patients required subsequent cardiac surgery (3% for re-

coarctation), 25% developed hypertension, and 15% had late cardiac-related deaths. Survival analysis showed that 91% of patients were alive at 10 years, decreasing to 72% at 30 years after repair. Death occurred at a mean age of 38 years, and was closely related to older age of repair (> 9 years of age), and post-operative hypertension. Forty-four percent of all late deaths were secondary to coronary artery disease or cerebrovascular accidents, indicating accelerated vascular disease.50 Similar results were reported by Toro-Salazar et al on 274 patients followed for more than 50 years.49 Risk of death after coarctation repair is estimated to be 3.8/1000 patient-year.64 An important risk factor for death is persistent hypertension, which is associated with older age of repair, and residual obstruction.50,65 Hypertension occurs in 7-28% of patients treated in infancy, compared to 38% treated at 4 years of age.36,50,51,52,53,57 The incidence of infective endocarditis after coarctation repair is 1.2/1000 patient-year, so prophylaxis should continue to be given.66

Conclusion COA is a lifelong disease with physiological changes that start in the fetal life, and continue into adulthood. Early management may reduce long-term complications, but close follow-up after treatment is warranted. References 1. Sinha SN, Kardatzke ML, Cole RB, et al.

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Health & Medicine

Coarctation of the aorta