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Imaging for coronary allograft vasculopathy in children and adolescents
Progress in Pediatric Cardiology 37 (2014) 29–35
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Review
Imaging for coronary allograft vasculopathy in children and adolescents Nathalie Dedieu, Tarique Hussain, Michael Burch ⁎ Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, United Kingdom
a r t i c l e
i n f o
Available online 24 October 2014 Keywords: Coronary allograft vasculopathy Angiography Intravascular ultrasound Magnetic resonance imaging
a b s t r a c t Cardiomyopathy is the main indication for pediatric heart transplantation. The major limitation on the long term survival after transplantation is coronary allograft vasculopathy (CAV). The usual method of diagnosis for CAV is coronary angiography. This is invasive and only detects late disease. Early disease may be detected with intravascular ultrasound or optical coherence tomography. Physiological assessment can be with fractional flow reserve or coronary flow reserve. The latter is more accurate in CAV. These tests are all invasive. Non-invasive testing with echocardiography has been used, particularly with stress testing but this can be difficult in children and international standards are not agreed. Non-invasive testing with Single Photon Emission Tomography Computed Tomography and Positron Emission Tomography have not been widely adopted in pediatrics but Computerised Tomography is becoming more common and can rival angiography. However all of these techniques use ionising radiation. Magnetic resonance imaging may be the future of pediatric coronary imaging as it is non-invasive, does not use ionising radiation, or nephrotoxic contrast, can image small and large vessels and can give accurate functional assessment. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Cardiomyopathy is the main indication for pediatric heart transplantation. Therefore it seems appropriate to consider in this section coronary allograft vasculopathy (CAV) which is the major limitation on long term survival after pediatric heart transplantation and is the main cause of mortality after the first year post transplant [1,2]. Endothelial injury from immunological and other causes results in intimal hyperplasia and luminal stenosis in major coronary vessels and small vessels. The disease can be predominantly epicardial, distal or both. As the lumen may be normal initially imaging of the vessel wall appears to be more helpful. Microvascular disease is present in heart transplant recipients early after transplant, even in asymptomatic patients [3,4] and it is known to be associated with CAV, ischemia and death. Imaging for CAV in children has been based on coronary angiography (Table 1). There are alternatives and this article aims to explore these. 1.1. Invasive Imaging Angiography and Intravascular Ultrasound (IVUS) and Optical Coherence Tomography (OCT) The diffuse nature of CAV is quite different to atherosclerosis and the rate of progression is much faster. Ischemia will develop but as the heart is denervated post-transplant it may be silent and sudden death can occur. The International Society of Heart and Lung Transplant registry data shows that survival after the diagnosis of CAV is poor with a ⁎ Corresponding author. E-mail addresses: [email protected] (N. Dedieu), [email protected] (M. Burch).
http://dx.doi.org/10.1016/j.ppedcard.2014.10.007 1058-9813/© 2014 Elsevier Ireland Ltd. All rights reserved.
2 year graft survival of less than 50% [2]. However the diagnosis in this registry data is made with angiography and this lumen imaging is likely to detect CAV much later than vessel wall imaging with intravascular ultrasound. Early diagnosis would enable targeted therapies and perhaps the progression of endothelial dysfunction to vascular thickening to be arrested. The early use of sirolimus and everolimus has been shown to be of benefit in slowing progression of disease [5–9]. However, angiography remains almost universal as the screening method for CAV in children. A few centers offer additional intravascular ultrasound in children. In adults, it has been shown that approximately half of transplant recipients with normal coronaries on angiography have significant intimal thickening on intravascular ultrasound and it is the most sensitive method of assessing CAV [10,11] Fig. 1. Data from the Pediatric Heart Transplant Study group has shown that angiographic abnormality is present in 17% of children at 5 years post-transplant [1]. There are limited intravascular ultrasound data in children but they do show that angiography has a low sensitivity [12]. Positive remodeling occurs early after transplantation and initial angiography may be normal despite important wall thickening. Subsequently negative remodeling leads to stenosis [13]. Thickening demonstrated on IVUS is predictive of the future development of angiographically detectable disease. A change of intimal thickening ≥ 0.5 mm over the first year post-transplant predicts angiographic development of CAV and death at 5-years post-transplant [14,15]. The value of IVUS in predicting outcome in pediatrics has not been demonstrated probably because of the small number of studies. IVUS has a variable correlation with microvascular or small artery disease in biopsy specimens [11] IVUS is used in our pediatric department for imaging the left main and proximal left anterior descending. We analyze
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Table 1 ISHLT consensus grading for coronary allograft vasculopathy (Mehra et al., 2010). Grade 0 (Not significant) I (Mild)
II (Moderate)
III (Severe)
No detectable angiographic lesion Angiographic left main (LM) b50% stenosis, or primary vessel with maximal lesion of b70%, or any branch stenosis of b70% (including diffuse narrowing) Angiographic LM 50–69% stenosis, a single primary vessel ≥70% stenosis, or isolated branch stenosis of ≥70% in branches of 2 systems Angiographic LM ≥70%, or 2 or more primary vessels ≥70% stenosis, or isolated branch stenosis of ≥ 70% in all 3 systems, or mild/moderate angiographic disease with LVEF b45% or evidence of significant restrictive physiology (i.e. symptomatic heart failure with echocardiographic E to A velocity ratio N2) (N1.5 in children), shortened isovolumetric relaxation time (b60 msec), shortened deceleration time (b150 msec), or restrictive hemodynamic values (right atrial pressure N 12 mm Hg, pulmonary capillary wedge pressure N 25 mm Hg, cardiac index b 2 l/min/m2)
Table 2 Stanford score (severity based on the localization of the most severe disease). Grade
Severity
Intimal thickness
I II III
Minimal Mild Moderate
IV
Severe
b0.3 mm & b180° b0.3 mm & N180° 0.3–0.5 mm OR 0.5–1 mm & b180° N1 mm OR 0.5–1 mm & N180°
30 cross-section images taken at 1.5 mm intervals and identified by branch points. In addition to maximal intimal thickness, mean intimal thickness, and mean intimal index, Stanford grading score (Table 2), and percentage of atheroma are recorded. We also use a semi-automatic interactive edge detection software (QIVUS) to improve reproducibility of measurements [16]. While IVUS may be possible in patients ≥10 kg [12,17], most of our IVUS experience is actually in children over 30 kg. Optical Coherence Tomography (OCT) measures reflected light wave intensity to produce a high resolution tomographic image [18]. It may be helpful in atherosclerosis to determine whether lesions are lipid rich or calcified or intimal hyperplasia [19,20]. Similarly, in heart transplant patients, characterization of the plaque is possible [21,22] (Fig. 2), although it may not be superior to IVUS in diagnosing CAV [23]. 2. Invasive Assessment of Coronary Flow In adult atherosclerosis it is often useful to assess the physiological importance of a large vessel stenosis using fractional flow reserve (FFR) [24]. FFR is defined as the ratio of maximum flow in the presence of a stenosis to normal maximum flow. It is measured by measuring flow proximal and distal to a lesion under maximum hyperaemia using a pressure/flow wire. A normal value is 1.0 and a value of 0.75 indicates a 25% reduction in flow. However, in CAV the microvascular disease can make FFR inaccurate in assessing large vessel stenosis [3, 25,26]. The increase in myocardial blood flow in response to stress is another important physiological marker of atherosclerotic coronary disease. This is called the coronary flow reserve (CFR) and is the ratio of the myocardial blood flow at peak stress, or maximal vasodilatation, to the flow at rest. It can be a useful marker of microvascular dysfunction [27–29]. In adult transplant patients it may be a marker of poor prognosis [30], although this is not a consistent finding in multivariate analysis [31].
Fig. 1. (A, B and C) Coronary angiographies showing respectively RCA, LCX and LAD: No evident stenosis. (D) IVUS image showing intimal thickening of LAD in the 3 o'clock position in the same patient.
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Fig. 2. OCT and corresponding IVUS image: the left sided image shows a longitudinal cut of the coronary artery whereas the right sided image shows a transverse cut. Greater near detail on OCT that enables deductions regarding plaque composition when compared to IVUS.
In pediatric transplant recipients a decrease in CFR appears to correlate with biopsy measured small vessel disease [32]. However, it is not widely used because of the invasive nature and it can be very difficult to obtain good consistent signals with the Doppler flow wire in small children. CFR can be measured using Cardiac Magnetic Resonanace Imaging and is discussed below.
2.1. Non-invasive Imaging, Echocardiography While early detection is desirable, the use of invasive methods such as angiography and intravascular ultrasound is distressing for children. Non-invasive assessment for CAV is the goal for pediatric patients. Exercise testing is possible in older children, typically in those older than 7 years. Our own group has looked at metabolic exercise testing and heart rate recovery [33], which may be of some prognostic use. But non-invasive imaging has not been particularly successful in the past. Stress testing with echocardiography and dobutamine (DSE) can be very distressing for children and exercise echocardiography also needs good cooperation which is not possible in younger children. The sensitivity, specificity, positive predictive value and negative predictive value vary significantly among adult studies, however, there is a correlation with IVUS [34]. A normal DSE is reassuring as it has a high negative predictive value for any major adverse cardiovascular event. Thus DSE may enable less frequent invasive angiography/IVUS [34–38]. This appears to be true in pediatrics [39] but there is far greater variability in sensitivity, specificity, positive predictive value and negative predictive value [37,40,41]. There are no internationally agreed protocols in pediatrics. The sensitivity and specificity of stress
echocardiography are improved by using strain imaging, which can quantify regions of wall motion abnormality [42] Fig. 3. Exercise stress echocardiography (ESE) in adult patients does not consistently correlate with CAV [43,44] although more recent studies are encouraging [45]. Physiologic assessment of coronary flow is possible with echocardiography in adults using contrast-enhanced echocardiography with adenosine mediated hyperemia. Coronary flow reserve measured by contrast enhanced echocardiography has been shown to correlate with IVUS and major acute cardiac events [46,47]. This technique is difficult in children because of the small size of the coronary arteries. Tissue Doppler imaging (TDI) may be helpful in detecting CAV. Systolic TDI parameters at the basal lateral LV wall level showed the highest diagnostic accuracy. Peak systolic motion velocity (Sm) b10 cm/s has a high positive predictive value for CAV [48,49]. There is wide interobserver variability in these measurements, which appears to limit the diagnostic utility of TDI. Pediatric studies are limited and there is a poor correlation between TDI and hemodynamic assessment [50]. 3. Noninvasive Imaging Using Radiation Single Photon Emission Computed Tomography (SPECT) often with Tc-99 m-labeled tracer is an established test for myocardial perfusion in adult atherosclerosis [51] and can be used in a stress test. Analysis of the microvasculature via myocardial perfusion reserve may give an abnormal result despite minimal large vessel disease [52]. It does appear useful in prognostication for death or graft loss in CAV in adults when combined with stress testing [53–65]. There is very little experience
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Fig. 3. Strain analysis showing wall motion abnormalities in LAD territory and corresponding stenosis visible on angiography.
with SPECT in children and the use of radiation makes it less attractive. Myocardial perfusion reserve can also be measured with Positron Emission Tomography (PET) and this technique can also measure perfusion of the epicardial arteries and the microvasculature [66,67], and it has been used in transplant patients [68–70] and may correlate to IVUS [69]. However, it is not widely used and normal data are limited.
Multidetector Computed Tomography (MDCT) is now widely used in adult atherosclerosis to detect stenosis [71], although plaque may be more difficult to image [72,73]. In heart transplant patients it appears at least as good as angiography in identifying coronary stenosis with high sensitivity and specificity [74]. It may correlate with IVUSdetermined intimal thickness N0.5 mm, with variable but generally
Fig. 4. MDCT angiography showing LAD and 3D reconstruction showing left main with LAD and LCX.
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Fig. 5. MRI image of typical Infarct Pattern Late Gadoilinum Enhancement in inferior wall (RCA distribution).
lower sensitivity [75–78]. It has been used in pediatric transplant recipients [79]. While it is non-invasive it does require a low heart rate for adequate imaging which is a problem in pediatric transplant patients who often have heart rates of over 100/min. The repeated use of radiation and nephrotoxic contrast makes it less attractive for pediatric use Fig. 4. 3.1. Cardiac Magnetic Resonance Imaging Cardiac Magnetic Resonance Imaging (CMRI) has the great advantage of being radiation free which is clearly important in pediatrics. In adults
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CMRI can detect atherosclerotic plaque and epicardial coronary artery stenoses [80–82]. It has been used in pediatric coronary imaging, despite elevated heart rates with whole heart dual phase cardiac imaging [83–85]. Although CMRI is not as sensitive as MDCT in detecting stenosis it can provide functional assessment of wall motion, ventricular volumes, ejection fraction, and myocardial characterization. Interestingly, CFR can be determined using CMRI of the coronary sinus [86–88] and it is significantly decreased in transplant patients with severe CAV. This may prove to be an important tool in non-invasively evaluating coronary allograft vasculopathy in heart transplant recipients [89]. CMR also appears superior to SPECT in demonstrating perfusion defects and therefore can be used to prognosticate in adult atherosclerosis [90,91]. Myocardial perfusion reserve can be assessed using CMRI in adult CAV [92]. The great majority of patients with severe angiographic CAV have late gadolinium enhancement (LGE) pattern in the subendocardial region and silent myocardial infarction can be demonstrated in asymptomatic patients [93]. Infarct atypical patterns may also be seen in [94] Figs. 5 and 6. Our group has shown that high resolution LGE can be used to show vessel wall disease in CAV in children with good correlation with IVUS (Pearson coefficient 0.80 [P b 0.001] and 0.92 [P b 0.001], respectively). An enhancement diameter N 7.5 mm gave promising sensitivity and specificity values of 86% and 93%, respectively, for the detection of significant CAV. In an adult CAV study, CMRI-based myocardial perfusion reserve was independently predictive of both epicardial (IVUS) and microvascular components of CAV (using invasive flow physiology methods) and diagnostic performance was significantly higher than angiography [95]. 4. Conclusion Angiography is the most widely used imaging for CAV in pediatrics. Unfortunately it is invasive, costly, and exposes children to radiation and nephrotoxic contrast. It only images the lumen and cannot identify early disease. IVUS can identify vessel wall thickening but does expose
Fig. 6. MRI images of atypical infarct and corresponding coronary angiography.
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children to radiation and is not possible in small children. MDCT can image coronary stenosis but also exposes children to radiation and contrast injections. DSE may detect disease non-invasively but is not possible in small children. While there are few studies of MRI in CAV the available data suggests it will become an integral part of the assessment of pediatric CAV because of its non-invasive nature and the avoidance of radiation and contrast added to the ability to assess both small and large vessel diseases, silent ischemia and ventricular function. Early detection may prove to be important if the disease progression can be changed by the implementation of treatment with proliferation signal inhibitors such as sirolimus and everolimus.
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Contents lists available at ScienceDirect
Progress in Pediatric Cardiology journal homepage: www.elsevier.com/locate/ppedcard
Review
Imaging for coronary allograft vasculopathy in children and adolescents Nathalie Dedieu, Tarique Hussain, Michael Burch ⁎ Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, United Kingdom
a r t i c l e
i n f o
Available online 24 October 2014 Keywords: Coronary allograft vasculopathy Angiography Intravascular ultrasound Magnetic resonance imaging
a b s t r a c t Cardiomyopathy is the main indication for pediatric heart transplantation. The major limitation on the long term survival after transplantation is coronary allograft vasculopathy (CAV). The usual method of diagnosis for CAV is coronary angiography. This is invasive and only detects late disease. Early disease may be detected with intravascular ultrasound or optical coherence tomography. Physiological assessment can be with fractional flow reserve or coronary flow reserve. The latter is more accurate in CAV. These tests are all invasive. Non-invasive testing with echocardiography has been used, particularly with stress testing but this can be difficult in children and international standards are not agreed. Non-invasive testing with Single Photon Emission Tomography Computed Tomography and Positron Emission Tomography have not been widely adopted in pediatrics but Computerised Tomography is becoming more common and can rival angiography. However all of these techniques use ionising radiation. Magnetic resonance imaging may be the future of pediatric coronary imaging as it is non-invasive, does not use ionising radiation, or nephrotoxic contrast, can image small and large vessels and can give accurate functional assessment. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Cardiomyopathy is the main indication for pediatric heart transplantation. Therefore it seems appropriate to consider in this section coronary allograft vasculopathy (CAV) which is the major limitation on long term survival after pediatric heart transplantation and is the main cause of mortality after the first year post transplant [1,2]. Endothelial injury from immunological and other causes results in intimal hyperplasia and luminal stenosis in major coronary vessels and small vessels. The disease can be predominantly epicardial, distal or both. As the lumen may be normal initially imaging of the vessel wall appears to be more helpful. Microvascular disease is present in heart transplant recipients early after transplant, even in asymptomatic patients [3,4] and it is known to be associated with CAV, ischemia and death. Imaging for CAV in children has been based on coronary angiography (Table 1). There are alternatives and this article aims to explore these. 1.1. Invasive Imaging Angiography and Intravascular Ultrasound (IVUS) and Optical Coherence Tomography (OCT) The diffuse nature of CAV is quite different to atherosclerosis and the rate of progression is much faster. Ischemia will develop but as the heart is denervated post-transplant it may be silent and sudden death can occur. The International Society of Heart and Lung Transplant registry data shows that survival after the diagnosis of CAV is poor with a ⁎ Corresponding author. E-mail addresses: [email protected] (N. Dedieu), [email protected] (M. Burch).
http://dx.doi.org/10.1016/j.ppedcard.2014.10.007 1058-9813/© 2014 Elsevier Ireland Ltd. All rights reserved.
2 year graft survival of less than 50% [2]. However the diagnosis in this registry data is made with angiography and this lumen imaging is likely to detect CAV much later than vessel wall imaging with intravascular ultrasound. Early diagnosis would enable targeted therapies and perhaps the progression of endothelial dysfunction to vascular thickening to be arrested. The early use of sirolimus and everolimus has been shown to be of benefit in slowing progression of disease [5–9]. However, angiography remains almost universal as the screening method for CAV in children. A few centers offer additional intravascular ultrasound in children. In adults, it has been shown that approximately half of transplant recipients with normal coronaries on angiography have significant intimal thickening on intravascular ultrasound and it is the most sensitive method of assessing CAV [10,11] Fig. 1. Data from the Pediatric Heart Transplant Study group has shown that angiographic abnormality is present in 17% of children at 5 years post-transplant [1]. There are limited intravascular ultrasound data in children but they do show that angiography has a low sensitivity [12]. Positive remodeling occurs early after transplantation and initial angiography may be normal despite important wall thickening. Subsequently negative remodeling leads to stenosis [13]. Thickening demonstrated on IVUS is predictive of the future development of angiographically detectable disease. A change of intimal thickening ≥ 0.5 mm over the first year post-transplant predicts angiographic development of CAV and death at 5-years post-transplant [14,15]. The value of IVUS in predicting outcome in pediatrics has not been demonstrated probably because of the small number of studies. IVUS has a variable correlation with microvascular or small artery disease in biopsy specimens [11] IVUS is used in our pediatric department for imaging the left main and proximal left anterior descending. We analyze
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Table 1 ISHLT consensus grading for coronary allograft vasculopathy (Mehra et al., 2010). Grade 0 (Not significant) I (Mild)
II (Moderate)
III (Severe)
No detectable angiographic lesion Angiographic left main (LM) b50% stenosis, or primary vessel with maximal lesion of b70%, or any branch stenosis of b70% (including diffuse narrowing) Angiographic LM 50–69% stenosis, a single primary vessel ≥70% stenosis, or isolated branch stenosis of ≥70% in branches of 2 systems Angiographic LM ≥70%, or 2 or more primary vessels ≥70% stenosis, or isolated branch stenosis of ≥ 70% in all 3 systems, or mild/moderate angiographic disease with LVEF b45% or evidence of significant restrictive physiology (i.e. symptomatic heart failure with echocardiographic E to A velocity ratio N2) (N1.5 in children), shortened isovolumetric relaxation time (b60 msec), shortened deceleration time (b150 msec), or restrictive hemodynamic values (right atrial pressure N 12 mm Hg, pulmonary capillary wedge pressure N 25 mm Hg, cardiac index b 2 l/min/m2)
Table 2 Stanford score (severity based on the localization of the most severe disease). Grade
Severity
Intimal thickness
I II III
Minimal Mild Moderate
IV
Severe
b0.3 mm & b180° b0.3 mm & N180° 0.3–0.5 mm OR 0.5–1 mm & b180° N1 mm OR 0.5–1 mm & N180°
30 cross-section images taken at 1.5 mm intervals and identified by branch points. In addition to maximal intimal thickness, mean intimal thickness, and mean intimal index, Stanford grading score (Table 2), and percentage of atheroma are recorded. We also use a semi-automatic interactive edge detection software (QIVUS) to improve reproducibility of measurements [16]. While IVUS may be possible in patients ≥10 kg [12,17], most of our IVUS experience is actually in children over 30 kg. Optical Coherence Tomography (OCT) measures reflected light wave intensity to produce a high resolution tomographic image [18]. It may be helpful in atherosclerosis to determine whether lesions are lipid rich or calcified or intimal hyperplasia [19,20]. Similarly, in heart transplant patients, characterization of the plaque is possible [21,22] (Fig. 2), although it may not be superior to IVUS in diagnosing CAV [23]. 2. Invasive Assessment of Coronary Flow In adult atherosclerosis it is often useful to assess the physiological importance of a large vessel stenosis using fractional flow reserve (FFR) [24]. FFR is defined as the ratio of maximum flow in the presence of a stenosis to normal maximum flow. It is measured by measuring flow proximal and distal to a lesion under maximum hyperaemia using a pressure/flow wire. A normal value is 1.0 and a value of 0.75 indicates a 25% reduction in flow. However, in CAV the microvascular disease can make FFR inaccurate in assessing large vessel stenosis [3, 25,26]. The increase in myocardial blood flow in response to stress is another important physiological marker of atherosclerotic coronary disease. This is called the coronary flow reserve (CFR) and is the ratio of the myocardial blood flow at peak stress, or maximal vasodilatation, to the flow at rest. It can be a useful marker of microvascular dysfunction [27–29]. In adult transplant patients it may be a marker of poor prognosis [30], although this is not a consistent finding in multivariate analysis [31].
Fig. 1. (A, B and C) Coronary angiographies showing respectively RCA, LCX and LAD: No evident stenosis. (D) IVUS image showing intimal thickening of LAD in the 3 o'clock position in the same patient.
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Fig. 2. OCT and corresponding IVUS image: the left sided image shows a longitudinal cut of the coronary artery whereas the right sided image shows a transverse cut. Greater near detail on OCT that enables deductions regarding plaque composition when compared to IVUS.
In pediatric transplant recipients a decrease in CFR appears to correlate with biopsy measured small vessel disease [32]. However, it is not widely used because of the invasive nature and it can be very difficult to obtain good consistent signals with the Doppler flow wire in small children. CFR can be measured using Cardiac Magnetic Resonanace Imaging and is discussed below.
2.1. Non-invasive Imaging, Echocardiography While early detection is desirable, the use of invasive methods such as angiography and intravascular ultrasound is distressing for children. Non-invasive assessment for CAV is the goal for pediatric patients. Exercise testing is possible in older children, typically in those older than 7 years. Our own group has looked at metabolic exercise testing and heart rate recovery [33], which may be of some prognostic use. But non-invasive imaging has not been particularly successful in the past. Stress testing with echocardiography and dobutamine (DSE) can be very distressing for children and exercise echocardiography also needs good cooperation which is not possible in younger children. The sensitivity, specificity, positive predictive value and negative predictive value vary significantly among adult studies, however, there is a correlation with IVUS [34]. A normal DSE is reassuring as it has a high negative predictive value for any major adverse cardiovascular event. Thus DSE may enable less frequent invasive angiography/IVUS [34–38]. This appears to be true in pediatrics [39] but there is far greater variability in sensitivity, specificity, positive predictive value and negative predictive value [37,40,41]. There are no internationally agreed protocols in pediatrics. The sensitivity and specificity of stress
echocardiography are improved by using strain imaging, which can quantify regions of wall motion abnormality [42] Fig. 3. Exercise stress echocardiography (ESE) in adult patients does not consistently correlate with CAV [43,44] although more recent studies are encouraging [45]. Physiologic assessment of coronary flow is possible with echocardiography in adults using contrast-enhanced echocardiography with adenosine mediated hyperemia. Coronary flow reserve measured by contrast enhanced echocardiography has been shown to correlate with IVUS and major acute cardiac events [46,47]. This technique is difficult in children because of the small size of the coronary arteries. Tissue Doppler imaging (TDI) may be helpful in detecting CAV. Systolic TDI parameters at the basal lateral LV wall level showed the highest diagnostic accuracy. Peak systolic motion velocity (Sm) b10 cm/s has a high positive predictive value for CAV [48,49]. There is wide interobserver variability in these measurements, which appears to limit the diagnostic utility of TDI. Pediatric studies are limited and there is a poor correlation between TDI and hemodynamic assessment [50]. 3. Noninvasive Imaging Using Radiation Single Photon Emission Computed Tomography (SPECT) often with Tc-99 m-labeled tracer is an established test for myocardial perfusion in adult atherosclerosis [51] and can be used in a stress test. Analysis of the microvasculature via myocardial perfusion reserve may give an abnormal result despite minimal large vessel disease [52]. It does appear useful in prognostication for death or graft loss in CAV in adults when combined with stress testing [53–65]. There is very little experience
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Fig. 3. Strain analysis showing wall motion abnormalities in LAD territory and corresponding stenosis visible on angiography.
with SPECT in children and the use of radiation makes it less attractive. Myocardial perfusion reserve can also be measured with Positron Emission Tomography (PET) and this technique can also measure perfusion of the epicardial arteries and the microvasculature [66,67], and it has been used in transplant patients [68–70] and may correlate to IVUS [69]. However, it is not widely used and normal data are limited.
Multidetector Computed Tomography (MDCT) is now widely used in adult atherosclerosis to detect stenosis [71], although plaque may be more difficult to image [72,73]. In heart transplant patients it appears at least as good as angiography in identifying coronary stenosis with high sensitivity and specificity [74]. It may correlate with IVUSdetermined intimal thickness N0.5 mm, with variable but generally
Fig. 4. MDCT angiography showing LAD and 3D reconstruction showing left main with LAD and LCX.
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Fig. 5. MRI image of typical Infarct Pattern Late Gadoilinum Enhancement in inferior wall (RCA distribution).
lower sensitivity [75–78]. It has been used in pediatric transplant recipients [79]. While it is non-invasive it does require a low heart rate for adequate imaging which is a problem in pediatric transplant patients who often have heart rates of over 100/min. The repeated use of radiation and nephrotoxic contrast makes it less attractive for pediatric use Fig. 4. 3.1. Cardiac Magnetic Resonance Imaging Cardiac Magnetic Resonance Imaging (CMRI) has the great advantage of being radiation free which is clearly important in pediatrics. In adults
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CMRI can detect atherosclerotic plaque and epicardial coronary artery stenoses [80–82]. It has been used in pediatric coronary imaging, despite elevated heart rates with whole heart dual phase cardiac imaging [83–85]. Although CMRI is not as sensitive as MDCT in detecting stenosis it can provide functional assessment of wall motion, ventricular volumes, ejection fraction, and myocardial characterization. Interestingly, CFR can be determined using CMRI of the coronary sinus [86–88] and it is significantly decreased in transplant patients with severe CAV. This may prove to be an important tool in non-invasively evaluating coronary allograft vasculopathy in heart transplant recipients [89]. CMR also appears superior to SPECT in demonstrating perfusion defects and therefore can be used to prognosticate in adult atherosclerosis [90,91]. Myocardial perfusion reserve can be assessed using CMRI in adult CAV [92]. The great majority of patients with severe angiographic CAV have late gadolinium enhancement (LGE) pattern in the subendocardial region and silent myocardial infarction can be demonstrated in asymptomatic patients [93]. Infarct atypical patterns may also be seen in [94] Figs. 5 and 6. Our group has shown that high resolution LGE can be used to show vessel wall disease in CAV in children with good correlation with IVUS (Pearson coefficient 0.80 [P b 0.001] and 0.92 [P b 0.001], respectively). An enhancement diameter N 7.5 mm gave promising sensitivity and specificity values of 86% and 93%, respectively, for the detection of significant CAV. In an adult CAV study, CMRI-based myocardial perfusion reserve was independently predictive of both epicardial (IVUS) and microvascular components of CAV (using invasive flow physiology methods) and diagnostic performance was significantly higher than angiography [95]. 4. Conclusion Angiography is the most widely used imaging for CAV in pediatrics. Unfortunately it is invasive, costly, and exposes children to radiation and nephrotoxic contrast. It only images the lumen and cannot identify early disease. IVUS can identify vessel wall thickening but does expose
Fig. 6. MRI images of atypical infarct and corresponding coronary angiography.
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children to radiation and is not possible in small children. MDCT can image coronary stenosis but also exposes children to radiation and contrast injections. DSE may detect disease non-invasively but is not possible in small children. While there are few studies of MRI in CAV the available data suggests it will become an integral part of the assessment of pediatric CAV because of its non-invasive nature and the avoidance of radiation and contrast added to the ability to assess both small and large vessel diseases, silent ischemia and ventricular function. Early detection may prove to be important if the disease progression can be changed by the implementation of treatment with proliferation signal inhibitors such as sirolimus and everolimus.
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