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Assessment of Subendocardial Function With Myocardial Contrast Echocardiography⁎
JACC: CARDIOVASCULAR IMAGING
VOL. 1, NO. 3, 2008
© 2008 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-878X/08/$34.00
PUBLISHED BY ELSEVIER INC.
DOI:10.1016/j.jcmg.2008.03.005
EDITORIAL COMMENT
Assessment of Subendocardial Function With Myocardial Contrast Echocardiography* Thomas H. Marwick, MBBS, PHD, FACC Brisbane, Australia
The classical ischemic cascade anticipates perfusion disturbances to precede the development of wall motion abnormalities, but does not account for regional heterogeneity of both perfusion and function. In this issue of JACC: Cardiovascular Imaging, Xie et al. (1) examine the impact of subendocardial ischemia (identified using real-time myocardial contrast echocardiography [MCE]) on myocardial thickening during dobutamine stress echocardiography (DSE). The subendocardium is the crucible of myocardial dysfunction in many diseases. This part of the myocardium is furthest from the epicardial coronary vessels, compressed by the intracavitary pressure as well as the remainder of the myocardium, and characterized by different myocardial fiber orientation (and therefore contraction See page 271
vector) from the rest of the myocardium. The subendocardium is not only involved in ischemic heart disease, but also in hypertensive heart disease (2) and perhaps in small vessel disease (3,4). However, the ability to characterize subendocardial function and perfusion has— until recently— been limited. Myocardial contrast echocardiography is 1 of 2 new imaging techniques that may address the ability to examine subendocardial perfusion in clinical practice. Previous experimental studies of MCE during dipyridamole stress have shown a transmural gradient of flow when hyperemic flow was reduced
*Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology. From the University of Queensland, Brisbane, Australia. Supported in part by a Clinical Centre of Research Excellence award from the National Health and Medical Research Council of Australia.
by 75%, despite preservation of wall thickening (5). This discrepancy between subendocardial malperfusion and preserved function occurred over a small window— both subendocardial and subepicardial flow were preserved at 50% reduction of hyperemic flow, and at a 90% reduction of hyperemic flow, both were reduced. The work of Xie et al. (1) represents the clinical analog of these findings. The investigators studied 94 patients with normal resting function, 55 of whom had a significant left anterior descending coronary artery stenosis. Wall thickening was visually assessed after contrast destruction and during myocardial contrast replenishment. End-systolic and -diastolic images of the subendocardial defect and entire wall thickness were chosen to measure subendocardial and transmural wall thickening, respectively. The majority of defects were subendocardial, and most of these appeared to have normal transmural wall thickening, despite reduced subendocardial wall thickening. Although quantitative transmural wall thickening failed to augment relative to baseline in those with abnormal subendocardial perfusion, the investigators showed a trend in wall thickening between those with normal through reduced subendocardial wall thickening and those with transmural abnormalities of wall thickening. Myocardial contrast echocardiography has been shown to improve the sensitivity of stress echocardiography, as well as enhance the detection of coronary stenoses in the nonculprit territory (6). Although left ventricular opacification can be justified in patients with suboptimal image quality, the conventional wisdom is that myocardial contrast is not a useful or necessary adjunct to wall motion assessment in all stress echocardiograms. Many studies are clearly normal (no significant coronary disease) or clearly abnormal (significant disease, often in multiple vessels), and these extremes are
280
Marwick Editorial Comment
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 3, 2008 MAY 2008:279 – 81
easy to recognize and easy to show concordance between reviewers. Perfusion analysis has the most to offer in patients with intermediate lesion severity, where wall motion changes are subtle and may be missed. However, the results of this study suggest that MCE is effective in part because residual subepicardial thickening with dobutamine hides the functional effects of subendocardial ischemia. These findings could be an argument in favor of routine use of MCE during stress echocardiography. Unfortunately, although the combination of MCE with stress echocardiography may improve sensitivity (especially in those with stenoses of borderline severity or multivessel stenoses), this may be at the cost of lower specificity. As the enhancement of sensitivity relates largely to the better recognition of mild disease, which is often prognostically benign, failure to improve specificity may limit the costeffectiveness of MCE (7). This is an interesting and well-performed study, but the sensitivity of dobutamine stress in the study (57% during myocardial contrast replenishment) is less than usually reported (8) and warrants clarification. The quoted sensitivity reflects only the positivity in the left anterior descending territory, rather than the sensitivity for the study as a whole, which may have been positive due to a left circumflex or right coronary artery lesion. Moreover, the visual assessment of wall thickening includes not only amplitude but also timing, and the measurement of systolic thickening only at end-systole would have precluded the recognition of tardokinesis. However, even without measurement in a single frame, frame rates of 20 to 25 Hz are suboptimal for wall motion assessment. In addition, the study population had a number of patients with concentric left ventricular remodeling, which may compromise the sensitivity of wall motion analysis (9). Finally, bubble destruction in the apex may have led to overestimation of apical thickening. The extent to which subendocardial defects may account for false negative exercise echocardiograms is an important question that warrants
REFERENCES
1. Xie F, Dodla S, O’Leary E, Porter TR. Detection of subendocardial ischemia in the left anterior descending coronary artery territory with realtime myocardial contrast echocardiog-
attention. Despite its easier performance, the sensitivity of DSE is somewhat less than that of exercise echocardiography, and defect extent is often smaller (10). Relatively lower afterload and the potent inotropic stimulus may lead to reduced left ventricular cavity size, lower wall stress, and reduced sensitivity, especially among those with concentric remodeling. Therefore, DSE may represent the “worst case” scenario for this mismatch between perfusion and function, and exercise echocardiograms, with higher wall stress and more extensive defects, may have fewer instances where ischemia is limited to the subendocardium. Although this study has important implications for interpretation of DSE, the findings also support the use of MCE in the clinical assessment of subendocardial perfusion and function. Experimental studies have addressed these entities using microspheres and microcrystals (11), but these are not clinical tools. The spatial resolution of positron emission tomography and single photon emission tomography are not well suited to this work, although such data might be obtainable with image processing strategies. Cardiac magnetic resonance assessment of perfusion may be made semiquantitatively, based on the change of signal intensity over time (similar to the principles of MCE) during the hyperenhancement of hypoperfused tissue with the first pass of gadolinium, although there are noncontrast alternatives (12). Although more difficult to perform, the echocardiographic technique is easier to apply in the acute setting, more versatile in terms of the types of stress agents, and can be obtained in real time. The combination of regional perfusion with quantification of myocardial deformation in different layers and in different dimensions may enable this tool to be used to assess both transmural perfusion and functional gradients. Reprint requests and correspondence: Prof. Thomas H.
Marwick, University of Queensland Department of Medicine, Princess Alexandra Hospital, Ipswich Road, Brisbane, Qld 4012, Australia. E-mail: tmarwick@soms. uq.edu.au.
raphy during dobutamine stress echocardiography. J Am Coll Cardiol Img 2008;1:271– 8. 2. Lapu-Bula R, Ofili E. From hypertension to heart failure: role of nitric oxide-mediated endothelial dysfunction and emerging insights from
myocardial contrast echocardiography. Am J Cardiol 2007;99:7D–14D. 3. Panting JR, Gatehouse PD, Yang GZ et al. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. N Engl J Med 2002;346:1948–53.
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 3, 2008 MAY 2008:279 – 81
4. Vermeltfoort IA, Bondarenko O, Raijmakers PG et al. Is subendocardial ischaemia present in patients with chest pain and normal coronary angiograms? A cardiovascular MR study. Eur Heart J 2007;28: 1554 – 8. 5. Yao GH, Zhang C, Sun FR et al. Quantification of transmural gradient of blood flow in myocardial ischemia with real-time myocardial contrast echocardiography and dipyridamole stress test. Ultrasound Med Biol 2008; 34:22–30. 6. Dijkmans PA, Senior R, Becher H et al. Myocardial contrast echocardiography evolving as a clinically feasible technique for accurate, rapid, and safe assessment of myocardial perfusion:
the evidence so far. J Am Coll Cardiol 2006;48:2168 –77. 7. Moir S, Shaw L, Haluska B, Jenkins C, Marwick TH. Left ventricular opacification for the diagnosis of coronary artery disease with stress echocardiography: an angiographic study of incremental benefit and costeffectiveness. Am Heart J 2007;154: 510 – 8. 8. Armstrong WF, Zoghbi WA. Stress echocardiography: current methodology and clinical applications. J Am Coll Cardiol 2005;45:1739 – 47. 9. Yuda S, Khoury V, Marwick TH. Influence of wall stress and left ventricular geometry on the accuracy of dobutamine stress echocardiography. J Am Coll Cardiol 2002;40: 1311–9.
Marwick Editorial Comment
10. Marwick TH, D’Hondt AM, Mairesse GH et al. Comparative ability of dobutamine and exercise stress in inducing myocardial ischaemia in active patients. Br Heart J 1994;72: 31– 8. 11. Kaul S, Jayaweera AR, Glasheen WP, Villanueva FS, Gutgesell HP, Spotnitz WD. Myocardial contrast echocardiography and the transmural distribution of flow: a critical appraisal during myocardial ischemia not associated with infarction. J Am Coll Cardiol 1992;20: 1005–16. 12. Prasad SK, Lyne J, Chai P, Gatehouse P. Role of CMR in assessment of myocardial perfusion. Eur Radiol 2005;15 Suppl 2:B42–7.
281
VOL. 1, NO. 3, 2008
© 2008 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-878X/08/$34.00
PUBLISHED BY ELSEVIER INC.
DOI:10.1016/j.jcmg.2008.03.005
EDITORIAL COMMENT
Assessment of Subendocardial Function With Myocardial Contrast Echocardiography* Thomas H. Marwick, MBBS, PHD, FACC Brisbane, Australia
The classical ischemic cascade anticipates perfusion disturbances to precede the development of wall motion abnormalities, but does not account for regional heterogeneity of both perfusion and function. In this issue of JACC: Cardiovascular Imaging, Xie et al. (1) examine the impact of subendocardial ischemia (identified using real-time myocardial contrast echocardiography [MCE]) on myocardial thickening during dobutamine stress echocardiography (DSE). The subendocardium is the crucible of myocardial dysfunction in many diseases. This part of the myocardium is furthest from the epicardial coronary vessels, compressed by the intracavitary pressure as well as the remainder of the myocardium, and characterized by different myocardial fiber orientation (and therefore contraction See page 271
vector) from the rest of the myocardium. The subendocardium is not only involved in ischemic heart disease, but also in hypertensive heart disease (2) and perhaps in small vessel disease (3,4). However, the ability to characterize subendocardial function and perfusion has— until recently— been limited. Myocardial contrast echocardiography is 1 of 2 new imaging techniques that may address the ability to examine subendocardial perfusion in clinical practice. Previous experimental studies of MCE during dipyridamole stress have shown a transmural gradient of flow when hyperemic flow was reduced
*Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology. From the University of Queensland, Brisbane, Australia. Supported in part by a Clinical Centre of Research Excellence award from the National Health and Medical Research Council of Australia.
by 75%, despite preservation of wall thickening (5). This discrepancy between subendocardial malperfusion and preserved function occurred over a small window— both subendocardial and subepicardial flow were preserved at 50% reduction of hyperemic flow, and at a 90% reduction of hyperemic flow, both were reduced. The work of Xie et al. (1) represents the clinical analog of these findings. The investigators studied 94 patients with normal resting function, 55 of whom had a significant left anterior descending coronary artery stenosis. Wall thickening was visually assessed after contrast destruction and during myocardial contrast replenishment. End-systolic and -diastolic images of the subendocardial defect and entire wall thickness were chosen to measure subendocardial and transmural wall thickening, respectively. The majority of defects were subendocardial, and most of these appeared to have normal transmural wall thickening, despite reduced subendocardial wall thickening. Although quantitative transmural wall thickening failed to augment relative to baseline in those with abnormal subendocardial perfusion, the investigators showed a trend in wall thickening between those with normal through reduced subendocardial wall thickening and those with transmural abnormalities of wall thickening. Myocardial contrast echocardiography has been shown to improve the sensitivity of stress echocardiography, as well as enhance the detection of coronary stenoses in the nonculprit territory (6). Although left ventricular opacification can be justified in patients with suboptimal image quality, the conventional wisdom is that myocardial contrast is not a useful or necessary adjunct to wall motion assessment in all stress echocardiograms. Many studies are clearly normal (no significant coronary disease) or clearly abnormal (significant disease, often in multiple vessels), and these extremes are
280
Marwick Editorial Comment
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 3, 2008 MAY 2008:279 – 81
easy to recognize and easy to show concordance between reviewers. Perfusion analysis has the most to offer in patients with intermediate lesion severity, where wall motion changes are subtle and may be missed. However, the results of this study suggest that MCE is effective in part because residual subepicardial thickening with dobutamine hides the functional effects of subendocardial ischemia. These findings could be an argument in favor of routine use of MCE during stress echocardiography. Unfortunately, although the combination of MCE with stress echocardiography may improve sensitivity (especially in those with stenoses of borderline severity or multivessel stenoses), this may be at the cost of lower specificity. As the enhancement of sensitivity relates largely to the better recognition of mild disease, which is often prognostically benign, failure to improve specificity may limit the costeffectiveness of MCE (7). This is an interesting and well-performed study, but the sensitivity of dobutamine stress in the study (57% during myocardial contrast replenishment) is less than usually reported (8) and warrants clarification. The quoted sensitivity reflects only the positivity in the left anterior descending territory, rather than the sensitivity for the study as a whole, which may have been positive due to a left circumflex or right coronary artery lesion. Moreover, the visual assessment of wall thickening includes not only amplitude but also timing, and the measurement of systolic thickening only at end-systole would have precluded the recognition of tardokinesis. However, even without measurement in a single frame, frame rates of 20 to 25 Hz are suboptimal for wall motion assessment. In addition, the study population had a number of patients with concentric left ventricular remodeling, which may compromise the sensitivity of wall motion analysis (9). Finally, bubble destruction in the apex may have led to overestimation of apical thickening. The extent to which subendocardial defects may account for false negative exercise echocardiograms is an important question that warrants
REFERENCES
1. Xie F, Dodla S, O’Leary E, Porter TR. Detection of subendocardial ischemia in the left anterior descending coronary artery territory with realtime myocardial contrast echocardiog-
attention. Despite its easier performance, the sensitivity of DSE is somewhat less than that of exercise echocardiography, and defect extent is often smaller (10). Relatively lower afterload and the potent inotropic stimulus may lead to reduced left ventricular cavity size, lower wall stress, and reduced sensitivity, especially among those with concentric remodeling. Therefore, DSE may represent the “worst case” scenario for this mismatch between perfusion and function, and exercise echocardiograms, with higher wall stress and more extensive defects, may have fewer instances where ischemia is limited to the subendocardium. Although this study has important implications for interpretation of DSE, the findings also support the use of MCE in the clinical assessment of subendocardial perfusion and function. Experimental studies have addressed these entities using microspheres and microcrystals (11), but these are not clinical tools. The spatial resolution of positron emission tomography and single photon emission tomography are not well suited to this work, although such data might be obtainable with image processing strategies. Cardiac magnetic resonance assessment of perfusion may be made semiquantitatively, based on the change of signal intensity over time (similar to the principles of MCE) during the hyperenhancement of hypoperfused tissue with the first pass of gadolinium, although there are noncontrast alternatives (12). Although more difficult to perform, the echocardiographic technique is easier to apply in the acute setting, more versatile in terms of the types of stress agents, and can be obtained in real time. The combination of regional perfusion with quantification of myocardial deformation in different layers and in different dimensions may enable this tool to be used to assess both transmural perfusion and functional gradients. Reprint requests and correspondence: Prof. Thomas H.
Marwick, University of Queensland Department of Medicine, Princess Alexandra Hospital, Ipswich Road, Brisbane, Qld 4012, Australia. E-mail: tmarwick@soms. uq.edu.au.
raphy during dobutamine stress echocardiography. J Am Coll Cardiol Img 2008;1:271– 8. 2. Lapu-Bula R, Ofili E. From hypertension to heart failure: role of nitric oxide-mediated endothelial dysfunction and emerging insights from
myocardial contrast echocardiography. Am J Cardiol 2007;99:7D–14D. 3. Panting JR, Gatehouse PD, Yang GZ et al. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. N Engl J Med 2002;346:1948–53.
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 3, 2008 MAY 2008:279 – 81
4. Vermeltfoort IA, Bondarenko O, Raijmakers PG et al. Is subendocardial ischaemia present in patients with chest pain and normal coronary angiograms? A cardiovascular MR study. Eur Heart J 2007;28: 1554 – 8. 5. Yao GH, Zhang C, Sun FR et al. Quantification of transmural gradient of blood flow in myocardial ischemia with real-time myocardial contrast echocardiography and dipyridamole stress test. Ultrasound Med Biol 2008; 34:22–30. 6. Dijkmans PA, Senior R, Becher H et al. Myocardial contrast echocardiography evolving as a clinically feasible technique for accurate, rapid, and safe assessment of myocardial perfusion:
the evidence so far. J Am Coll Cardiol 2006;48:2168 –77. 7. Moir S, Shaw L, Haluska B, Jenkins C, Marwick TH. Left ventricular opacification for the diagnosis of coronary artery disease with stress echocardiography: an angiographic study of incremental benefit and costeffectiveness. Am Heart J 2007;154: 510 – 8. 8. Armstrong WF, Zoghbi WA. Stress echocardiography: current methodology and clinical applications. J Am Coll Cardiol 2005;45:1739 – 47. 9. Yuda S, Khoury V, Marwick TH. Influence of wall stress and left ventricular geometry on the accuracy of dobutamine stress echocardiography. J Am Coll Cardiol 2002;40: 1311–9.
Marwick Editorial Comment
10. Marwick TH, D’Hondt AM, Mairesse GH et al. Comparative ability of dobutamine and exercise stress in inducing myocardial ischaemia in active patients. Br Heart J 1994;72: 31– 8. 11. Kaul S, Jayaweera AR, Glasheen WP, Villanueva FS, Gutgesell HP, Spotnitz WD. Myocardial contrast echocardiography and the transmural distribution of flow: a critical appraisal during myocardial ischemia not associated with infarction. J Am Coll Cardiol 1992;20: 1005–16. 12. Prasad SK, Lyne J, Chai P, Gatehouse P. Role of CMR in assessment of myocardial perfusion. Eur Radiol 2005;15 Suppl 2:B42–7.
281