Journal of the American College of Cardiology Ó 2014 by the American College of Cardiology Foundation Published by Elsevier Inc.
EDITORIAL COMMENT
The 30-Year Road of Noninvasive Imaging for Congenital Aortic Stenosis New Insights From Cardiac Magnetic Resonance Imaging* Beth Feller Printz, MD, PHD San Diego, California
Patients with congenital aortic stenosis (AS) have a broad clinical spectrum, ranging from critically-ill newborns to asymptomatic adults. Combined Doppler and 2-dimensional echocardiographic assessment of critical neonatal AS was introduced 30 years ago (1). Since then, evaluation of disease severity in a young AS patient has been primarily on the basis of symptoms and echocardiographic parameters (2), but echocardiographic measurements are only the tip of the iceberg when assessing the impact of AS on the myocardium itself. See page 1778
The common denominator in AS is chronic pressure load on the left ventricle (LV). Concentric hypertrophy develops as the LV attempts to normalize wall stress, but LV remodeling with fibrosis can occur (3,4). Historically, the only way to directly assess fibrosis has been by biopsy, which may not be representative of the entire LV and is impractical in the clinical setting. One instead evaluates the consequences of fibrosis using surrogate echocardiographic parameters. In adult AS patients, there are correlations among LV dysfunction, ventricular fibrosis, and poorer prognosis (3,5–7). Children with AS post-intervention may have symptoms, diastolic dysfunction, and fibrosis despite “adequate” relief of obstruction (2,8,9); whether fibrosis in childhood AS correlates with prognosis is unclear, and findings from adults cannot be extrapolated to children for 2 reasons. First, although the etiology of AS in older adults is usually degenerative (10), AS in children is almost always *Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Division of Cardiology, Rady Children’s Hospital San Diego, and the Department of Pediatrics, University of California San Diego, San Diego, California. Dr. Printz has reported that she has no relationships relevant to the contents of this paper to disclose.
Vol. 63, No. 17, 2014 ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2013.12.051
congenital. Second, ventricular remodeling in children may be quite different than in adults (11). For example, in some cases of prenatally-diagnosed severe AS, the LV involutes over a few weeks from a dilated, poorly-contracting cavity into a fibrotic shell. If AS is relieved through fetal intervention by balloon valvuloplasty, development of hypoplastic left heart syndrome can potentially be prevented (12). Focal Ventricular Fibrosis and Cardiac Magnetic Resonance Cardiac magnetic resonance (CMR) has recently been promoted as a noninvasive technique to directly assess ventricular fibrosis in lieu of biopsy. Focal fibrosis can be detected by CMR as areas of increased signal intensity on post-contrast late gadolinium enhancement (LGE) imaging, with LGE pattern depending on the etiology of fibrosis (4). The degree of focal fibrosis detected by LGE in older adults with AS has been shown to correlate with histologic fibrosis and poorer outcome post-intervention (5,13). Circumferential subendocardial LGE consistent with endocardial fibroelastosis has also been described in young congenital AS patients and confirmed on pathology (14,15). The 4 cases reported by Robinson et al. (15) are particularly intriguing, as these teenagers all had remote, “successful” procedures to relieve severe AS, but each presented with symptomatic diastolic heart disease. Diffuse Fibrosis and CMR Because LGE is on the basis of nulling “normal” myocardium to demonstrate a difference in signal intensity between normal and fibrotic regions, LGE imaging is insensitive to diffuse fibrosis. Recently, a CMR T1 mapping technique was introduced to assess diffuse myocardial fibrosis by measuring myocardial and blood pool longitudinal relaxation time (T1) before and after gadolinium contrast (16), with changes in T1 values used to calculate extracellular volume fraction (ECV) (17). CMR-derived ECV has been shown to correlate with myocardial fibrosis in animal models (18) and in older adults with cardiovascular diseases (4) including AS (19). The paper by Dusenbery et al. (20) in this issue of the Journal is the first study reporting the use of CMR-derived ECV to measure diffuse LV fibrosis in young subjects with congenital AS and to explore the relationship between CMRderived measures of fibrosis and clinical and echocardiographic data. In this retrospective, case-control study, the authors compared ECV measured by CMR in 35 children and young adults with congenital AS with ECV measurements in 27 normal controls. They found that mean ECV (i.e., degree of diffuse fibrosis) was higher in the AS patients versus control subjects, but there was significant overlap between the 2 groups such that only 37% of congenital AS patients had abnormal ECV. LGE was observed in about one-fourth of the AS patients. Both ECV and LGE were associated with abnormal echocardiographic diastolic
JACC Vol. 63, No. 17, 2014 May 6, 2014:1786–7
function indexes but not with current AS gradient or with LV diastolic assessment in those patients with contemporaneous catheterization data. As this was a retrospective study, not all AS patients had complete echocardiograms, catheterization, or exercise tests within 1 year of CMR. Also, although the patients were a heterogeneous group, this group may not be representative of the spectrum of congenital AS patients, as only those referred for CMR were included. Eighty percent of their patients had undergone prior interventions, only one-half were below 16 years of age at the time of CMR, and 83% were male. Despite these limitations, this study confirms that myocardial fibrosis can persist despite what appears to be adequate relief of obstruction in young congenital AS patients, as has previously been found in older adults. Moreover, this study demonstrates the feasibility of ECV assessment in children. T1 mapping is a potentially very powerful technique, but further validation and standardization is needed (4,18,21). There are currently several T1 mapping methods; T1 maps generated by 1 method may not be equivalent to those generated by another. T1 mapping may be influenced by several technical factors, including gadolinium dose and wash-in/wash-out dynamics, heart rate and motion, and magnet strength. There are also patient-specific variables such as age, size, sex, and genetic heterogeneities that may affect T1 measurement. After this CMR T1 mapping technique is validated and standardized, it could potentially be used to monitor disease progression and/or regression and optimize management of congenital AS patients. One could theoretically use CMR to investigate whether there is a vulnerable period in cardiac development when the myocardium is particularly sensitive to pressure overload or to develop therapeutics directly targeting reversible fibrosis (22). It is also possible that other CMR techniques will help define ventricular response to congenital AS. For example, diffusion tensor MRI has recently been used to demonstrate “developmental plasticity” in cardiomyocyte architecture between fetal, neonatal, and adult periods (23). Perhaps soon T1 mapping and other CMR techniques will be ready for “prime time,” 30 years down the road of noninvasive imaging for congenital AS. Reprint requests and correspondence: Dr. Beth Feller Printz, Rady Children’s Hospital San Diego, 3020 Children’s Way, MC 5004, San Diego, California 92123. E-mail: [email protected].
Printz Congenital Aortic Stenosis: Insights From CMR
4. 5. 6.
7. 8. 9.
10. 11. 12.
13.
14.
15.
16. 17.
18. 19. 20.
21. REFERENCES
1. Robinson PJ, Wyse RK, Deanfield JE, Franklin R, Macartney FJ. Continuous wave Doppler velocimetry as an adjunct to cross sectional echocardiography in the diagnosis of critical left heart obstruction in neonates. Br Heart J 1984;52:552–6. 2. Friedman KG, McElhinney DB, Colan SD, et al. Left ventricular remodeling and improvement in diastolic function after balloon aortic valvuloplasty for congenital aortic stenosis. Circ Cardiovasc Interv 2012;5:549–54. 3. Heymans S, Schroen B, Vermeersch P, et al. Increased cardiac expression of tissue inhibitor of metalloproteinase-1 and tissue inhibitor of
22. 23.
1787
metalloproteinase-2 is related to cardiac fibrosis and dysfunction in the chronic pressure-overloaded human heart. Circulation 2005;112:1126–44. Mewton N, Liu CY, Croisille P, Bluemke D, Lima JAC. Assessment of myocardial fibrosis with cardiovascular magnetic resonance. J Am Coll Cardiol 2011;57:891–903. Weidemann F, Herrmann S, Störk S, et al. Impact of myocardial fibrosis in patients with symptomatic severe aortic stenosis. Circulation 2009;120:577–84. Yarbrough WM, Mukherjee R, Ikonomidis JS, Zile MR, Spinale FG. Myocardial remodeling with aortic stenosis and following aortic valve replacement-mechanisms and future prognostic implications. J Thorac Cardiovasc Surg 2012;143:656–64. Milano AD, Faggian G, Dodonov M, et al. Prognostic value of myocardial fibrosis in patients with severe aortic valve stenosis. J Thorac Cardiovasc Surg 2012;144:830–7. Kipps AK, McElhinney DB, Kane J, Rhodes J. Exercise function of children with congenital aortic stenosis following aortic valvuloplasty during early infancy. Congenit Heart Dis 2009;4:258–64. Robinson JD, del Nido PJ, Geggel RL, Perez-Atayde AR, Lock JE, Powell AJ. Left ventricular diastolic heart failure in teenagers who underwent balloon aortic valvuloplasty in early infancy. Am J Cardiol 2010;106:426–9. Towler DA. Molecular aspects of calcific aortic valve disease. Circ Res 2013;113:198–208. Eghtesady P, Michelfelder E, Altaye M, Ballard E, Hirsh R, Beekman RH. Revisiting animal models of aortic stenosis in the early gestation fetus. Ann Thorac Surg 2007;83:631–9. Tworetzky W, Wilkins-Haug L, Jennings RW, et al. Balloon dilation of severe aortic stenosis in the fetus: potential for prevention of hypoplastic left heart syndrome: candidate selection, technique, and results of successful intervention. Circulation 2004;110:2125–31. Azevedo CF, Nigri M, Higuchi ML, et al. Prognostic significance of myocardial fibrosis quantification by histopathology and magnetic resonance imaging in patients with severe aortic valve disease. J Am Coll Cardiol 2010;56:278–87. Tworetzky W, del Nido PJ, Powell AJ, Marshall AC, Lock JE, Geva T. Usefulness of magnetic resonance imaging of left ventricular endocardial fibroelastosis after fetal intervention for aortic valve stenosis. Am J Cardiol 2005;96:1568–70. Robinson JD, del Nido PJ, Geggel RL, Perez-Atayde AR, Lock JE, Powell AJ. Left ventricular diastolic heart failure in teenagers who underwent balloon aortic valvuloplasty in early infancy. Am J Cardiol 2010;106:425–9. Messroghli DR, Niendorf T, Schulz-Menger J, Dietz R, Friedrich MG. T1 mapping in patients with acute myocardial infarction. J Cardiovasc Magn Reson 2003;5:353–9. Broberg CS, Chugh SS, Conklin C, Sahn DJ, Jerosch-Herold M. Quantification of diffuse myocardial fibrosis and its association with myocardial dysfunction in congenital heart disease. Circ Cardiovasc Imaging 2010;3:727–34. Neilan TG, Coelho-Filho OR, Shah RV, et al. Myocardial extracellular volume fraction from T1 measurements in healthy volunteers and mice. J Am Coll Cardiol Img 2013;6:672–83. Flett AS, Hawyard MP, Ashworth MT, et al. Equilibrium contrast cardiovascular magnetic resonance for the measurement of diffuse myocardial fibrosis: preliminary validation in humans. Circulation 2010;122:138–44. Dusenbery SM, Jerosch-Herold M, Rickers C, et al. Myocardial extracellular remodeling is associated with ventricular diastolic dysfunction in children and young adults with congenital aortic stenosis. J Am Coll Cardiol 2014;63:1778–85. Moon JC, Messroghi DR, Kellman P, et al. Myocardial T1 mapping and extracellular volume quantification: a Society for Cardiovascular Magnetic Resonance (SCMR) and CMR Working Group of the European Society of Cardiology consensus statement. J Cardiovasc Magn Reson 2013;15:92–103. Towbin JA. Scarring in the heartda reversible phenomenon? N Engl J Med 2007;357:1767–8. Zhang L, Allen J, Hu L, Caruthers SD, Wickline SA, Chen J. Cardiomyocyte architectural plasticity in fetal, neonatal, and adult pig hearts delineated with diffusion tensor MRI. Am J Physiol Heart Circ Physiol 2013;304:H246–52.
Key Words: congenital aortic stenosis myocardial fibrosis.
-
magnetic resonance imaging
-
EDITORIAL COMMENT
The 30-Year Road of Noninvasive Imaging for Congenital Aortic Stenosis New Insights From Cardiac Magnetic Resonance Imaging* Beth Feller Printz, MD, PHD San Diego, California
Patients with congenital aortic stenosis (AS) have a broad clinical spectrum, ranging from critically-ill newborns to asymptomatic adults. Combined Doppler and 2-dimensional echocardiographic assessment of critical neonatal AS was introduced 30 years ago (1). Since then, evaluation of disease severity in a young AS patient has been primarily on the basis of symptoms and echocardiographic parameters (2), but echocardiographic measurements are only the tip of the iceberg when assessing the impact of AS on the myocardium itself. See page 1778
The common denominator in AS is chronic pressure load on the left ventricle (LV). Concentric hypertrophy develops as the LV attempts to normalize wall stress, but LV remodeling with fibrosis can occur (3,4). Historically, the only way to directly assess fibrosis has been by biopsy, which may not be representative of the entire LV and is impractical in the clinical setting. One instead evaluates the consequences of fibrosis using surrogate echocardiographic parameters. In adult AS patients, there are correlations among LV dysfunction, ventricular fibrosis, and poorer prognosis (3,5–7). Children with AS post-intervention may have symptoms, diastolic dysfunction, and fibrosis despite “adequate” relief of obstruction (2,8,9); whether fibrosis in childhood AS correlates with prognosis is unclear, and findings from adults cannot be extrapolated to children for 2 reasons. First, although the etiology of AS in older adults is usually degenerative (10), AS in children is almost always *Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Division of Cardiology, Rady Children’s Hospital San Diego, and the Department of Pediatrics, University of California San Diego, San Diego, California. Dr. Printz has reported that she has no relationships relevant to the contents of this paper to disclose.
Vol. 63, No. 17, 2014 ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2013.12.051
congenital. Second, ventricular remodeling in children may be quite different than in adults (11). For example, in some cases of prenatally-diagnosed severe AS, the LV involutes over a few weeks from a dilated, poorly-contracting cavity into a fibrotic shell. If AS is relieved through fetal intervention by balloon valvuloplasty, development of hypoplastic left heart syndrome can potentially be prevented (12). Focal Ventricular Fibrosis and Cardiac Magnetic Resonance Cardiac magnetic resonance (CMR) has recently been promoted as a noninvasive technique to directly assess ventricular fibrosis in lieu of biopsy. Focal fibrosis can be detected by CMR as areas of increased signal intensity on post-contrast late gadolinium enhancement (LGE) imaging, with LGE pattern depending on the etiology of fibrosis (4). The degree of focal fibrosis detected by LGE in older adults with AS has been shown to correlate with histologic fibrosis and poorer outcome post-intervention (5,13). Circumferential subendocardial LGE consistent with endocardial fibroelastosis has also been described in young congenital AS patients and confirmed on pathology (14,15). The 4 cases reported by Robinson et al. (15) are particularly intriguing, as these teenagers all had remote, “successful” procedures to relieve severe AS, but each presented with symptomatic diastolic heart disease. Diffuse Fibrosis and CMR Because LGE is on the basis of nulling “normal” myocardium to demonstrate a difference in signal intensity between normal and fibrotic regions, LGE imaging is insensitive to diffuse fibrosis. Recently, a CMR T1 mapping technique was introduced to assess diffuse myocardial fibrosis by measuring myocardial and blood pool longitudinal relaxation time (T1) before and after gadolinium contrast (16), with changes in T1 values used to calculate extracellular volume fraction (ECV) (17). CMR-derived ECV has been shown to correlate with myocardial fibrosis in animal models (18) and in older adults with cardiovascular diseases (4) including AS (19). The paper by Dusenbery et al. (20) in this issue of the Journal is the first study reporting the use of CMR-derived ECV to measure diffuse LV fibrosis in young subjects with congenital AS and to explore the relationship between CMRderived measures of fibrosis and clinical and echocardiographic data. In this retrospective, case-control study, the authors compared ECV measured by CMR in 35 children and young adults with congenital AS with ECV measurements in 27 normal controls. They found that mean ECV (i.e., degree of diffuse fibrosis) was higher in the AS patients versus control subjects, but there was significant overlap between the 2 groups such that only 37% of congenital AS patients had abnormal ECV. LGE was observed in about one-fourth of the AS patients. Both ECV and LGE were associated with abnormal echocardiographic diastolic
JACC Vol. 63, No. 17, 2014 May 6, 2014:1786–7
function indexes but not with current AS gradient or with LV diastolic assessment in those patients with contemporaneous catheterization data. As this was a retrospective study, not all AS patients had complete echocardiograms, catheterization, or exercise tests within 1 year of CMR. Also, although the patients were a heterogeneous group, this group may not be representative of the spectrum of congenital AS patients, as only those referred for CMR were included. Eighty percent of their patients had undergone prior interventions, only one-half were below 16 years of age at the time of CMR, and 83% were male. Despite these limitations, this study confirms that myocardial fibrosis can persist despite what appears to be adequate relief of obstruction in young congenital AS patients, as has previously been found in older adults. Moreover, this study demonstrates the feasibility of ECV assessment in children. T1 mapping is a potentially very powerful technique, but further validation and standardization is needed (4,18,21). There are currently several T1 mapping methods; T1 maps generated by 1 method may not be equivalent to those generated by another. T1 mapping may be influenced by several technical factors, including gadolinium dose and wash-in/wash-out dynamics, heart rate and motion, and magnet strength. There are also patient-specific variables such as age, size, sex, and genetic heterogeneities that may affect T1 measurement. After this CMR T1 mapping technique is validated and standardized, it could potentially be used to monitor disease progression and/or regression and optimize management of congenital AS patients. One could theoretically use CMR to investigate whether there is a vulnerable period in cardiac development when the myocardium is particularly sensitive to pressure overload or to develop therapeutics directly targeting reversible fibrosis (22). It is also possible that other CMR techniques will help define ventricular response to congenital AS. For example, diffusion tensor MRI has recently been used to demonstrate “developmental plasticity” in cardiomyocyte architecture between fetal, neonatal, and adult periods (23). Perhaps soon T1 mapping and other CMR techniques will be ready for “prime time,” 30 years down the road of noninvasive imaging for congenital AS. Reprint requests and correspondence: Dr. Beth Feller Printz, Rady Children’s Hospital San Diego, 3020 Children’s Way, MC 5004, San Diego, California 92123. E-mail: [email protected].
Printz Congenital Aortic Stenosis: Insights From CMR
4. 5. 6.
7. 8. 9.
10. 11. 12.
13.
14.
15.
16. 17.
18. 19. 20.
21. REFERENCES
1. Robinson PJ, Wyse RK, Deanfield JE, Franklin R, Macartney FJ. Continuous wave Doppler velocimetry as an adjunct to cross sectional echocardiography in the diagnosis of critical left heart obstruction in neonates. Br Heart J 1984;52:552–6. 2. Friedman KG, McElhinney DB, Colan SD, et al. Left ventricular remodeling and improvement in diastolic function after balloon aortic valvuloplasty for congenital aortic stenosis. Circ Cardiovasc Interv 2012;5:549–54. 3. Heymans S, Schroen B, Vermeersch P, et al. Increased cardiac expression of tissue inhibitor of metalloproteinase-1 and tissue inhibitor of
22. 23.
1787
metalloproteinase-2 is related to cardiac fibrosis and dysfunction in the chronic pressure-overloaded human heart. Circulation 2005;112:1126–44. Mewton N, Liu CY, Croisille P, Bluemke D, Lima JAC. Assessment of myocardial fibrosis with cardiovascular magnetic resonance. J Am Coll Cardiol 2011;57:891–903. Weidemann F, Herrmann S, Störk S, et al. Impact of myocardial fibrosis in patients with symptomatic severe aortic stenosis. Circulation 2009;120:577–84. Yarbrough WM, Mukherjee R, Ikonomidis JS, Zile MR, Spinale FG. Myocardial remodeling with aortic stenosis and following aortic valve replacement-mechanisms and future prognostic implications. J Thorac Cardiovasc Surg 2012;143:656–64. Milano AD, Faggian G, Dodonov M, et al. Prognostic value of myocardial fibrosis in patients with severe aortic valve stenosis. J Thorac Cardiovasc Surg 2012;144:830–7. Kipps AK, McElhinney DB, Kane J, Rhodes J. Exercise function of children with congenital aortic stenosis following aortic valvuloplasty during early infancy. Congenit Heart Dis 2009;4:258–64. Robinson JD, del Nido PJ, Geggel RL, Perez-Atayde AR, Lock JE, Powell AJ. Left ventricular diastolic heart failure in teenagers who underwent balloon aortic valvuloplasty in early infancy. Am J Cardiol 2010;106:426–9. Towler DA. Molecular aspects of calcific aortic valve disease. Circ Res 2013;113:198–208. Eghtesady P, Michelfelder E, Altaye M, Ballard E, Hirsh R, Beekman RH. Revisiting animal models of aortic stenosis in the early gestation fetus. Ann Thorac Surg 2007;83:631–9. Tworetzky W, Wilkins-Haug L, Jennings RW, et al. Balloon dilation of severe aortic stenosis in the fetus: potential for prevention of hypoplastic left heart syndrome: candidate selection, technique, and results of successful intervention. Circulation 2004;110:2125–31. Azevedo CF, Nigri M, Higuchi ML, et al. Prognostic significance of myocardial fibrosis quantification by histopathology and magnetic resonance imaging in patients with severe aortic valve disease. J Am Coll Cardiol 2010;56:278–87. Tworetzky W, del Nido PJ, Powell AJ, Marshall AC, Lock JE, Geva T. Usefulness of magnetic resonance imaging of left ventricular endocardial fibroelastosis after fetal intervention for aortic valve stenosis. Am J Cardiol 2005;96:1568–70. Robinson JD, del Nido PJ, Geggel RL, Perez-Atayde AR, Lock JE, Powell AJ. Left ventricular diastolic heart failure in teenagers who underwent balloon aortic valvuloplasty in early infancy. Am J Cardiol 2010;106:425–9. Messroghli DR, Niendorf T, Schulz-Menger J, Dietz R, Friedrich MG. T1 mapping in patients with acute myocardial infarction. J Cardiovasc Magn Reson 2003;5:353–9. Broberg CS, Chugh SS, Conklin C, Sahn DJ, Jerosch-Herold M. Quantification of diffuse myocardial fibrosis and its association with myocardial dysfunction in congenital heart disease. Circ Cardiovasc Imaging 2010;3:727–34. Neilan TG, Coelho-Filho OR, Shah RV, et al. Myocardial extracellular volume fraction from T1 measurements in healthy volunteers and mice. J Am Coll Cardiol Img 2013;6:672–83. Flett AS, Hawyard MP, Ashworth MT, et al. Equilibrium contrast cardiovascular magnetic resonance for the measurement of diffuse myocardial fibrosis: preliminary validation in humans. Circulation 2010;122:138–44. Dusenbery SM, Jerosch-Herold M, Rickers C, et al. Myocardial extracellular remodeling is associated with ventricular diastolic dysfunction in children and young adults with congenital aortic stenosis. J Am Coll Cardiol 2014;63:1778–85. Moon JC, Messroghi DR, Kellman P, et al. Myocardial T1 mapping and extracellular volume quantification: a Society for Cardiovascular Magnetic Resonance (SCMR) and CMR Working Group of the European Society of Cardiology consensus statement. J Cardiovasc Magn Reson 2013;15:92–103. Towbin JA. Scarring in the heartda reversible phenomenon? N Engl J Med 2007;357:1767–8. Zhang L, Allen J, Hu L, Caruthers SD, Wickline SA, Chen J. Cardiomyocyte architectural plasticity in fetal, neonatal, and adult pig hearts delineated with diffusion tensor MRI. Am J Physiol Heart Circ Physiol 2013;304:H246–52.
Key Words: congenital aortic stenosis myocardial fibrosis.
-
magnetic resonance imaging
-
