A 23-year-old man was seen for difficult-to-control hypertension. On initial presentation he had a blood pressure (BP) of 160/90 mm Hg. Despite initiation of multiple antihypertensive medications including hydrochlorothiazide and lisinopril, the patient remained hypertensive with systolic BP of greater than 140 mm Hg. The patient was asymptomatic but reported a lifelong murmur. Physical examination revealed a right upper extremity BP of 146/82 mm Hg. Cardiovascular examination was significant for a grade II/VI systolic ejection murmur and a posterior systolic murmur in the left infrascapular region. Lower extremity pulses were diminished. A transthoracic echocardiogram demonstrated a bicuspid aortic valve, mild aortic dilation, and flow acceleration across the aortic isthmus.

CASE EXPLANATION

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  This patient has coarctation of the aorta (CoA) and its most common manifestation is systemic arterial hypertension.

  
  
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  Patients with CoA often present in infancy with congestive heart failure.¹ However, those who escape diagnosis in childhood most commonly present with difficult-to-control hypertension later in life.

  
  
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  This patient also had a bicuspid aortic valve (BAV) which is present in approximately 50% to 60% of patients with CoA.

  
  
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  Aortic dilation along with a BAV can also be seen in such patients.

EPIDEMIOLOGY

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  The incidence of CoA is approximately 0.3 per 1000 live births^{2, 3} and accounts for approximately 5% to 8% of congenital heart disease making it the eighth most common congenital heart defect.^{4, 5}

  
  
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  CoA, like other forms of left-sided heart obstruction, is more common in males than females.⁴

  
  
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  While CoA can be isolated, it often coexists with other forms of heart disease: Of patients with simple CoA, 42% have a patent ductus arteriosus. Approximately 50% to 60% of patients with CoA have bicommissural aortic valve (BAV). Approximately 10% have an intracranial aneurysm.^{6, 7}

  
  
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  CoA often coexists with other forms of left heart obstruction including mitral stenosis, subaortic stenosis, and aortic stenosis. In addition, CoA is associated with atrial septal defects, ventricular septal defects, and complex congenital heart disease (eg, hypoplastic left heart syndrome, atrioventricular canal defect, transposition of the great arteries).³

  
  
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  Women with Turner syndrome (gonadal dysgenesis with 45,X karyotype) have an increased risk (12%-35%) of CoA.^{8, 9, 10}

ETIOLOGY

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  The etiology of CoA is multifactorial and incompletely understood.

  
  
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  There is a compelling evidence for a genetic contribution to CoA.^{11, 12, 13, 14} CoA is more common in the children of women with CoA.¹⁵ The genetics is not simple, however, while NOTCH1 mutations have been described in patients with CoA, this mutation is absent in most patients.¹⁶ Linkage analysis has identified multiple candidate genes¹⁷ although progress has been hindered by the relative rarity of the disorder and phenotypic variability. As CoA often coexists with other forms of left heart obstruction, as described above, some have speculated whether CoA, BAV, and other forms of left-sided obstruction are different phenotypic manifestations of the same disease process.¹⁸

  
  
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  Seasonal variability is present with peak incidence in spring and fall suggesting a possible role of infection or other unidentified environmental factors.¹⁹

  
  
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  Environmental risk factors may play a role in the pathogenesis, including organic solvents, although this has not been confirmed.²⁰

  
  
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  Traditionally, the etiology of CoA was thought to be due to either incomplete regression of ductal tissue causing aortic constriction or reduced aortic growth in response to inadequate anterograde flow.²¹ CoA is now known to be part of a diffuse arteriopathy with abnormalities throughout the pre-coarctation arterial tree.⁶

ANATOMY

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  Most commonly CoA is a discrete fibrotic posterior ridge or shelf which narrows the aorta at the insertion of the ductus arteriosus—called juxtaductal (Figure 3-1).

  
  
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  Anatomic variations exist including discrete CoA, long-segment CoA, hypoplastic aortic arch in association with CoA.

  
  
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  Histologic changes to the arterial tree include cystic medial necrosis, elastic tissue fragmentation, smooth muscle hypertrophy, and loss of elastic fibers. These changes are found throughout the arterial tree and are not merely a response to pressure load.^{22, 23, 24}

  
  
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  Often vascular function is abnormal, with impaired endothelium-dependent and endothelium-independent vasoreactivity with abnormal vasodilation in response to flow and exogenous nitric oxide.^{25, 26}

PATHOPHYSIOLOGY

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  CoA causes upper extremity hypertension which can result in hypertension and left ventricular hypertrophy.

  
  
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  Hypertension affects 25% to 75% of patients with repaired CoA.^{27, 28, 29, 30, 31, 32, 33, 34, 35} Age at repair is an important determinant of late hypertension.

  
  
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  In several studies, those who are repaired during infancy have a less than 5% chance of developing hypertension by early adulthood while those operated on after the age of 1 had a 25% to 33% chance of developing hypertension early in life.^{28, 29, 36}

  
  
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  Late hypertension is strongly associated with residual or recurrent aortic arch obstruction.³⁰ Therefore, in patients with repaired CoA who present with hypertension, residual obstruction must be excluded.³⁷

  
  
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  Nonetheless, some patients with early repair and no residual arch obstruction still develop hypertension due to vascular dysfunction (discussed later). For example, in a study of 119 children repaired in early infancy, 19% of patients with no residual arch obstruction had an ambulatory blood pressure greater than the 95th percentile.³⁰

  
  
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  Patients with CoA have diffuse arterial disease manifested by increased vascular stiffness, decreased arterial elasticity, and impaired endothelial function.^{6, 26, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46} The mechanisms underlying hypertension in these patients is complex. Reduced vascular compliance and accelerated pulse wave velocity contribute to augmentation of systolic blood pressure via reflected waves which fall in systole.^{42, 47} Additionally, stiff proximal conduit arteries fail to dampen pulsatile flow thereby raising vascular impedance and ventricular afterload.⁴⁸

  
  
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  When the left ventricle is coupled to abnormal vasculature, remodeling occurs.^{48, 49} Increased pressure results in left ventricular hypertrophy in order to normalize wall strain.⁵⁰ Ventricular systolic stiffness increases and, in combination with the increased arterial elastance, contributes to hypertension both at rest and with adrenergic stimulation.³⁹

  
  
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  Hypertension can lead to cardiovascular events as early as the third and fourth decade. Patients with repaired CoA are at increased risk for premature myocardial infarction, cerebrovascular accidents, dissection, left ventricular systolic dysfunction, and endocarditis.^{28, 51} However, with increased recognition of late hypertension and treatment of modifiable risk factors³⁷ the incidence of premature cardiovascular disease in this population may be improving.^{52, 53}

  
  
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  The prevalence of hypertension also depends on how blood pressure is measured and the age of the population is studied. In one study, ambulatory blood pressure measurement diagnosed hypertension in 54% of patients with repaired CoA while resting BP detected hypertension in only 21%.³⁸

DIAGNOSIS

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  The diagnosis of CoA depends on appropriate clinical suspicion. Not all patients with hypertension require imaging of the aorta to exclude CoA as the physical examination can diagnose a hemo-dynamically significant CoA in most patients.

Physical Examination

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  Measurement of the blood pressure in the arm and leg with the patient in a supine position should be performed. Normally the lower extremity blood pressure is 10% to 20% higher than the upper extremity blood pressure due to wave amplification.⁵⁴ If leg blood pressure is substantially lower (10 mm Hg) than arm BP then CoA or other forms of peripheral arterial disease should be suspected. A gradient of greater than 35 mm Hg has a very high specificity for CoA.⁵⁵ Collateral vessels which bridge the region of CoA are common so blood pressure gradient may not be very high even in patients with hemodynamically important CoA.

  
  
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  Simultaneous palpitation of right radial and femoral arteries should also be performed if CoA is suspected. If femoral pulse is weak or delayed in relation to the radial pulse then CoA should be suspected and imaging should be performed.

  
  
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  A systolic or continuous murmur over the back may be present in patients with CoA.

  
  
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  As more than 5% of patients with bicommissural aortic valve have CoA, all patients with bicommissural aortic valve should be evaluated for CoA. A careful physical examination may be adequate to exclude CoA but echocardiography or cross-sectional imaging of the thoracic aorta with magnetic resonance (MR) or computed tomography (CT) angiography is reasonable.³⁷

Echocardiography

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  Transthoracic echocardiography (TTE) is widely available but has significant limitations in the evaluation of CoA. Suprasternal acoustic windows are often difficult in the adult and the distance between the transducer and the aortic isthmus make echocardiographic imaging challenging. Nonetheless, the directed goals of the TTE are listed in Table 3-1 should be to evaluate the aortic isthmus, hemodynamic significance of the gradient across the CoA, and aortic aneurysms (either proximal or distal to the CoA). The left subclavian artery should be identified from long-axis views and the proximal descending thoracic aorta should be imaged to evaluate for narrowing and poststenotic dilation (Figure 3-2). Use of a low-frequency imaging probe and harmonic imaging can improve 2D imaging of the aortic isthmus.

  
  
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  Spectral Doppler across the CoA is valuable but has potential pitfalls. From the suprasternal window continuous Doppler can be used to estimate gradient across CoA. As in all applications of spectral Doppler, the beam must be aligned with the direction of flow.

  
  
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  Qualitative assessment of the continuous-wave Doppler signal across the CoA provides valuable information about the degree of obstruction: high maximum velocity across the isthmus with prolonged diastolic deceleration phase (Figure 3-3). Caution must be used in analyzing this pattern as alterations in arterial compliance, common in patients with CoA, can alter the appearance such that stiffer conduit arteries accelerate the pressure decay and potentially mask a hemodynamically significant CoA.⁵⁶

  
  
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  The modified Bernoulli equation (pressure gradient = 4v²) often overestimates the pressure gradient measured at the time of cardiac catheterization.^{57, 58} The accuracy of continuous-wave Doppler estimation of gradients across the isthmus can be improved by expanding the modified Bernoulli equation to include the proximal velocity measured by pulse-wave Doppler (v₁) such that pressure gradient = 4(v₂²–v₁²).^{58, 59} The presence of significant collateral arteries bridging the CoA can cause spectral Doppler to under-estimate the severity of obstruction.⁶⁰ Very severe obstruction, stiff arteries, long, torturous, or eccentric gradients can also lead to misleading Doppler estimation of gradient.^{56, 57, 61, 62}

  
  
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  Abdominal aortic flow pattern provides important information on severity of obstruction. When a pulse-wave Doppler sample is placed in the abdominal aorta in patients without aortic obstruction, there is a rapid systolic upstroke, a short deceleration time, a brief early diastolic flow reversal, and little anterograde flow throughout diastole (Figure 3-4).^{63, 64, 65} Loss of early diastolic flow reversal is highly sensitive for the detection of upstream stenosis. Blunted systolic velocity, continuous anterograde flow, and increased diastolic flow velocity in the abdominal aorta are important indicators of aortic obstruction. A greater than 50-ms delay between the R-wave and the peak velocity in the abdominal aorta is also associated with significant CoA.⁶³ Prolonged deceleration time also indicated significant upstream obstruction.⁶

Magnetic Resonance Imaging

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  Magnetic resonance (MR) imaging has emerged as a comprehensive method to evaluate CoA. MR provides anatomic data, is not limited by acoustic windows, and does not expose the patient to ionizing radiation which is an important concern in young patients who will need to undergo serial examinations.

  
  
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  Black blood double-inversion recovery spin echo imaging in the long-axis images provides static images with excellent anatomic definition of the CoA (Figure 3-5). Black blood images are less susceptible to artifact from implanted metallic devices than other MR techniques.

  
  
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  Balanced steady-state free precession (bright blood cine) images also provide good anatomic detail and can show turbulence across the region of CoA. These cine images are also used to evaluate for the hemodynamic consequence of chronic pressure overload such as alterations in left ventricular size, mass, and systolic function.³⁵

  
  
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  Phase-contrast MR provides information about the quantity, direction, and velocity of blood flow. As is true in Doppler echocardiography, high-velocity flow across the CoA is likely indicative of a significant obstruction but precise measurement of gradients is difficult. A high-velocity encoding (VENC) setting may be required. The degree of collateral circulation can be quantified using phase-contrast MR techniques. A sample can be obtained just proximal to the CoA to determine the volume per beat. A second sample is obtained at the diaphragm. In patients without collateral vessels the flow at the diaphragm should be slightly lower than the flow proximal to the CoA due to blood sent to the intercostal and bronchial arteries. However, in patients with significant collaterals the flow at the diaphragm will be higher than the flow proximal to the CoA.^{66, 67, 68} Analysis of the pattern of phase-contrast MR in the descending thoracic aorta at the level of the diaphragm provides information similar to that obtained by pulse-wave Doppler in the abdominal aorta. A long rate-corrected diastolic deceleration time is associated with hemodynamically significant CoA^{69, 70} (Figure 3-6).

  
  
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  Gadolinium-enhanced MR angiography provides useful information regarding CoA anatomy, proximity to brachiocephalic vessels, aneurysmal disease, and collaterals (Figures 3-7A and 3-7B). Multiplanar reconstructions should be used to evaluate lumen diameter (Figure 3-8). Maximum-intensity projections (MIP) and 3-dimensional, volume-rendered reconstructions provide an anatomic roadmap for surgical or transcatheter therapy (Figure 3-9).

  
  
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  Four-dimensional (4D) phase contrast is an emerging technique which can combine anatomic information with flow mapping to quantify collateral flow and visualize blood flow in 3 dimensions throughout the cardiac cycle.⁷¹

  
  
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  Approximately 10% of patients with CoA have cerebral aneurysms.^{7, 72} The natural history and clinical significance of these aneurysms are unknown. Magnetic resonance angiography to search for intracranial aneurysms is appropriate.³⁷ The optimal age for screening and frequency of reevaluation is unknown.