Editorial Novel Magnetic Resonance Imaging End Points for Physiologic Studies in Peripheral Arterial Disease Elegance Versus Practicality Christopher M. Kramer, MD
P
eripheral arterial disease (PAD) remains the somewhat forgotten atherosclerotic vascular disease despite its high prevalence1 and association with significant cardiovascular morbidity and mortality. It is understudied relative to coronary artery and cerebrovascular disease and there are few guideline-based effective medical therapies.2 Exercise is one promising, yet underutilized therapy,3 and newer therapies, such as stem cell4 and gene therapies,5 are being gradually developed and tested. One of the limitations to the development of novel therapies is that there remains a paucity of validated and reproducible techniques to measure their effectiveness. The ankle brachial index (ABI) is an excellent screening technique to establish the presence of PAD,6 but it is insensitive to changes from therapies other than those that alter bulk arterial flow, such as percutaneous revascularization. Thus, the ABI is not particularly useful for studies of novel medical, stem cell, or gene therapies. Similarly, treadmill exercise performance and 6-minute walking times are dependent on patient effort, are not particularly reproducible, and thus imperfect for use in such studies. Even experts in the field cannot agree on which of these 2 exercise tests are most useful for studies in PAD.7,8
However, because of the complexities of modeling tissue blood flow, absolute quantification of blood flow is not yet possible with this technique, although it remains a long-term goal. A noncontrast technique termed arterial spin labeling (ASL), a method developed in the early 1990s for measuring blood flow in the brain,12 does enable absolute flow quantification and avoids the use of gadolinium contrast. Wu et al13 applied continuous ASL to the measurement of time to peak perfusion during hyperemia and showed that it tracked with severity of PAD as measured by ABI. Our group applied pulsed ASL for the same purpose, but at peak exercise, demonstrating differences in peak perfusion between patients with PAD and matched controls.14 We recently showed that cuff occlusion hyperemia ASL measures were more reproducible than peak exercise measures in controls and patients with PAD, likely because of both differences in patient effort and in muscles used during plantar flexion exercise.15 Bloodoxygen-level–dependent MRI is yet another technique that measures tissue oxygenation and has been applied to PAD to show both lower peak change during postocclusion hyperemia and delayed recovery relative to controls.16 These prior studies set the stage for the one in the current issue of Circulation: Cardiovascular Imaging.17 This group of investigators has been developing novel MRI methods in PAD for several years. In addition to ASL, they have studied blood-oxygen-level–dependent MRI and venous blood oxygenation,18 all using the cuff occlusion hyperemia paradigm. They subsequently put these MRI approaches together into a single MRI pulse sequence, combining measures of Perfusion, IntraVenous Oxygen saturation, and T2* (equivalent to bloodoxygen-level–dependent) or PIVOT that was piloted in healthy controls during cuff occlusion and hyperemia.19 PIVOT has a temporal resolution of 2 seconds and thus can measure the kinetics of perfusion, venous oxygenation, and T2*. In this study, the authors studied 96 patients with PAD with a broad range of ABI and 10 healthy controls with PIVOT. Peak values for perfusion were all lower and time to peak perfusion and T2* longer in PAD than controls. Increases in time to peak for all 3 measures correlated inversely to the ABI. However, peak perfusion values did not correspond to the ABI, which is not surprising because the ABI measures bulk arterial flow and does not take collateral flow into account. The authors demonstrate that the most reliable measures were time to peak perfusion and time to peak T2*. PIVOT is an elegant technique and was carefully studied. The question remains, is it practical and useful for clinical trials? One of the strengths and, consequently, drawbacks of MRI is its technological versatility. Physicists and engineers
See Article by Englund et al To fill this void, several investigative groups have been recently developing novel magnetic resonance imaging (MRI) and magnetic resonance spectroscopic techniques aimed for use in clinical trials. 31Phosphorus magnetic resonance spectroscopy can be used to measure phosphocreatine recovery kinetics in the calf musculature at end exercise as a sensitive marker of ischemia9 and it correlates with treadmill walking time10 and as such may be used as a surrogate marker. However, 31 P magnetic resonance spectroscopy is not widely available which limits its potential use. First-pass contrast-enhanced MRI at peak exercise can be applied to quantify a semiquantitative calf muscle perfusion index normalized to the arterial input function11 and it correlates with 6-minute walk distance.10
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Departments of Medicine and Radiology, University of Virginia Health System, Charlottesville. Correspondence to Christopher M. Kramer, MD, Cardiovascular Imaging Center, University of Virginia Health System, Lee St, Box 800170, Charlottesville, VA 22908. E-mail [email protected] (Circ Cardiovasc Imaging. 2015;8:e003360. DOI: 10.1161/CIRCIMAGING.115.003360.) © 2015 American Heart Association, Inc. irc Cardiovasc Imaging is available at C http://circimaging.ahajournals.org DOI: 10.1161/CIRCIMAGING.115.003360
1
2 Kramer Novel MRI Endpoints in PAD can constantly develop exciting new pulse sequences that enable characterization of physiology in a myriad of ways. At times, innovation gets in the way of practicality. If the field is trying to develop techniques for use in clinical trials that can be implemented in a multicenter fashion and on scanners from different vendors, then simpler approaches using 1 reproducible technique may be more practical. The other question that must be raised, are 3 measures truly better than 1? The venous blood oxygenation measure may not stand the test of time as it was only able to be measured in 77% of cases and was the least reproducible of the 3. In addition, one must ask whether time to peak perfusion is really measuring different physiology than time to peak T2*? Peak perfusion was measured in different muscle groups, whereas T2* was measured through the entire calf. Neither end point was correlated with walking performance in this study, so we do not know whether 1 is more physiologically meaningful than the other. In addition, the reproducibility of both measures, especially in patients with PAD, was modest and inferior to absolute peak ASL perfusion measures recently published.15 The authors suggest that the changes between time points in the same individual may be measuring clinically relevant changes, but 3 months is a relatively short-time frame for physiology of PAD to change significantly without an interval intervention. If one was designing a clinical trial and performing power analyses to minimize the n to study in each group, the most reproducible measure would be the most attractive. As the authors point out, the PIVOT measures may be best for measuring differences between groups, but perhaps not in a patient over time or with a particular intervention. PAD is stepwise becoming a more robustly studied atherosclerotic vascular disease. The number of potential therapeutic interventions is steadily growing as is the number of potential surrogate end points for clinical trials for these interventions. The next step must be multicenter implementation of the techniques that are deemed most useful, practical, and reproducible. Only then will the field of testing these interventions fully mature. In the meantime, exciting novel approaches continue to develop, aimed at improved the understanding of the pathophysiology of PAD and serving as a window into atherosclerosis and its downstream effects.
Disclosures Dr Kramer is supported by R01 HL075792 and U01HL117006-01A1 and receives research equipment support from Siemens Healthcare.
References 1. Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, Norman PE, Sampson UK, Williams LJ, Mensah GA, Criqui MH. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet. 2013;382:1329–1340. doi: 10.1016/S0140-6736(13)61249-0. 2. Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, Findeiss LK, Golzarian J, Gornik HL, Halperin JL, Jaff MR, Moneta GL, Olin JW, Stanley JC, White CJ, White JV, Zierler RE; Society for Cardiovascular Angiography and Interventions; Society of Interventional Radiology; Society for Vascular Medicine; Society for Vascular Surgery. 2011 ACCF/ AHA Focused Update of the Guideline for the Management of Patients With Peripheral Artery Disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart
Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011;58:2020–2045. doi: 10.1016/j.jacc.2011.08.023. 3. Murphy TP, Cutlip DE, Regensteiner JG, Mohler ER III, Cohen DJ, Reynolds MR, Massaro JM, Lewis BA, Cerezo J, Oldenburg NC, Thum CC, Jaff MR, Comerota AJ, Steffes MW, Abrahamsen IH, Goldberg S, Hirsch AT. Supervised exercise, stent revascularization, or medical therapy for claudication due to aortoiliac peripheral artery disease: the CLEVER study. J Am Coll Cardiol. 2015;65:999–1009. doi: 10.1016/j. jacc.2014.12.043. 4. Poole J, Mavromatis K, Binongo JN, Khan A, Li Q, Khayata M, Rocco E, Topel M, Zhang X, Brown C, Corriere MA, Murrow J, Sher S, Clement S, Ashraf K, Rashed A, Kabbany T, Neuman R, Morris A, Ali A, Hayek S, Oshinski J, Yoon YS, Waller EK, Quyyumi AA. Effect of progenitor cell mobilization with granulocyte-macrophage colony-stimulating factor in patients with peripheral artery disease: a randomized clinical trial. JAMA. 2013;310:2631–2639. doi: 10.1001/jama.2013.282540. 5. Annex BH. Therapeutic angiogenesis for critical limb ischaemia. Nat Rev Cardiol. 2013;10:387–396. doi: 10.1038/nrcardio.2013.70. 6. Aboyans V, Criqui MH, Abraham P, Allison MA, Creager MA, Diehm C, Fowkes FG, Hiatt WR, Jönsson B, Lacroix P, Marin B, McDermott MM, Norgren L, Pande RL, Preux PM, Stoffers HE, Treat-Jacobson D; American Heart Association Council on Peripheral Vascular Disease; Council on Epidemiology and Prevention; Council on Clinical Cardiology; Council on Cardiovascular Nursing; Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery and Anesthesia. Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association. Circulation. 2012;126:2890–2909. doi: 10.1161/CIR.0b013e318276fbcb. 7. McDermott MM, Guralnik JM, Criqui MH, Liu K, Kibbe MR, Ferrucci L. Six-minute walk is a better outcome measure than treadmill walking tests in therapeutic trials of patients with peripheral artery disease. Circulation. 2014;130:61–68. doi: 10.1161/CIRCULATIONAHA.114.007002. 8. Hiatt WR, Rogers RK, Brass EP. The treadmill is a better functional test than the 6-minute walk test in therapeutic trials of patients with peripheral artery disease. Circulation. 2014;130:69–78. doi: 10.1161/ CIRCULATIONAHA.113.007003. 9. Isbell DC, Berr SS, Toledano AY, Epstein FH, Meyer CH, Rogers WJ, Harthun NL, Hagspiel KD, Weltman A, Kramer CM. Delayed calf muscle phosphocreatine recovery after exercise identifies peripheral arterial disease. J Am Coll Cardiol. 2006;47:2289–2295. doi: 10.1016/j. jacc.2005.12.069. 10. Anderson JD, Epstein FH, Meyer CH, Hagspiel KD, Wang H, Berr SS, Harthun NL, Weltman A, Dimaria JM, West AM, Kramer CM. Multifactorial determinants of functional capacity in peripheral arterial disease: uncoupling of calf muscle perfusion and metabolism. J Am Coll Cardiol. 2009;54:628–635. doi: 10.1016/j.jacc.2009.01.080. 11. Isbell DC, Epstein FH, Zhong X, DiMaria JM, Berr SS, Meyer CH, Rogers WJ, Harthun NL, Hagspiel KD, Weltman A, Kramer CM. Calf muscle perfusion at peak exercise in peripheral arterial disease: measurement by first-pass contrast-enhanced magnetic resonance imaging. J Magn Reson Imaging. 2007;25:1013–1020. doi: 10.1002/jmri.20899. 12. Williams DS, Detre JA, Leigh JS, Koretsky AP. Magnetic resonance imaging of perfusion using spin inversion of arterial water. Proc Natl Acad Sci U S A. 1992;89:212–216. 13. Wu WC, Mohler E III, Ratcliffe SJ, Wehrli FW, Detre JA, Floyd TF. Skeletal muscle microvascular flow in progressive peripheral artery disease: assessment with continuous arterial spin-labeling perfusion magnetic resonance imaging. J Am Coll Cardiol. 2009;53:2372–2377. doi: 10.1016/j.jacc.2009.03.033. 14. Pollak AW, Meyer CH, Epstein FH, Jiji RS, Hunter JR, Dimaria JM, Christopher JM, Kramer CM. Arterial spin labeling MR imaging reproducibly measures peak-exercise calf muscle perfusion: a study in patients with peripheral arterial disease and healthy volunteers. JACC Cardiovasc Imaging. 2012;5:1224–1230. doi: 10.1016/j.jcmg.2012.03.022. 15. Lopez D, Pollak AW, Meyer CH, Epstein FH, Pesch AJ, Jiji RS, Kay JR, Dimaria JM, Christopher JM, Kramer CM. Arterial spin labeling calf perfusion CMR in peripheral arterial disease: cuff occlusion hyperemia vs. exercise. J Cardiovasc Magn Reson. 2015;17:23. doi:10.1186/s12968-015-0128-y. 16. Ledermann HP, Schulte AC, Heidecker HG, Aschwanden M, Jäger KA, Scheffler K, Steinbrich W, Bilecen D. Blood oxygenation level-dependent magnetic resonance imaging of the skeletal muscle in patients with peripheral arterial occlusive disease. Circulation. 2006;113:2929–2935. doi: 10.1161/CIRCULATIONAHA.105.605717. 17. Englund EK, Langham MC, Ratcliffe SJ, Fanning MJ, Wehrli FW, Mohler ER III, Floyd TF. Multiparametric assessment of vascular function in periph-
3 Kramer Novel MRI Endpoints in PAD eral artery disease: dynamic measurement of skeletal muscle perfusion, bloodoxygen-level dependent signal, and venous oxygen saturation. Circ Cardiovasc Imaging. 2015;8:e002673. doi: 10.1161/CIRCIMAGING.114.002673. 18. Langham MC, Floyd TF, Mohler ER III, Magland JF, Wehrli FW. Evaluation of cuff-induced ischemia in the lower extremity by magnetic resonance oximetry. J Am Coll Cardiol. 2010;55:598–606. doi: 10.1016/j. jacc.2009.08.068.
19. Englund EK, Langham MC, Li C, Rodgers ZB, Floyd TF, Mohler ER, Wehrli FW. Combined measurement of perfusion, venous oxygen saturation, and skeletal muscle T2* during reactive hyperemia in the leg. J Cardiovasc Magn Reson. 2013;15:70. doi: 10.1186/1532-429X-15-70. Key Words: Editorials ◼ magnetic resonance imaging ◼ perfusion ◼ peripheral arterial disease ◼ peripheral vascular diseases
Novel Magnetic Resonance Imaging End Points for Physiologic Studies in Peripheral Arterial Disease: Elegance Versus Practicality Christopher M. Kramer Circ Cardiovasc Imaging. 2015;8: doi: 10.1161/CIRCIMAGING.115.003360 Circulation: Cardiovascular Imaging is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 1941-9651. Online ISSN: 1942-0080
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circimaging.ahajournals.org/content/8/4/e003360
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation: Cardiovascular Imaging can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation: Cardiovascular Imaging is online at: http://circimaging.ahajournals.org//subscriptions/
P
eripheral arterial disease (PAD) remains the somewhat forgotten atherosclerotic vascular disease despite its high prevalence1 and association with significant cardiovascular morbidity and mortality. It is understudied relative to coronary artery and cerebrovascular disease and there are few guideline-based effective medical therapies.2 Exercise is one promising, yet underutilized therapy,3 and newer therapies, such as stem cell4 and gene therapies,5 are being gradually developed and tested. One of the limitations to the development of novel therapies is that there remains a paucity of validated and reproducible techniques to measure their effectiveness. The ankle brachial index (ABI) is an excellent screening technique to establish the presence of PAD,6 but it is insensitive to changes from therapies other than those that alter bulk arterial flow, such as percutaneous revascularization. Thus, the ABI is not particularly useful for studies of novel medical, stem cell, or gene therapies. Similarly, treadmill exercise performance and 6-minute walking times are dependent on patient effort, are not particularly reproducible, and thus imperfect for use in such studies. Even experts in the field cannot agree on which of these 2 exercise tests are most useful for studies in PAD.7,8
However, because of the complexities of modeling tissue blood flow, absolute quantification of blood flow is not yet possible with this technique, although it remains a long-term goal. A noncontrast technique termed arterial spin labeling (ASL), a method developed in the early 1990s for measuring blood flow in the brain,12 does enable absolute flow quantification and avoids the use of gadolinium contrast. Wu et al13 applied continuous ASL to the measurement of time to peak perfusion during hyperemia and showed that it tracked with severity of PAD as measured by ABI. Our group applied pulsed ASL for the same purpose, but at peak exercise, demonstrating differences in peak perfusion between patients with PAD and matched controls.14 We recently showed that cuff occlusion hyperemia ASL measures were more reproducible than peak exercise measures in controls and patients with PAD, likely because of both differences in patient effort and in muscles used during plantar flexion exercise.15 Bloodoxygen-level–dependent MRI is yet another technique that measures tissue oxygenation and has been applied to PAD to show both lower peak change during postocclusion hyperemia and delayed recovery relative to controls.16 These prior studies set the stage for the one in the current issue of Circulation: Cardiovascular Imaging.17 This group of investigators has been developing novel MRI methods in PAD for several years. In addition to ASL, they have studied blood-oxygen-level–dependent MRI and venous blood oxygenation,18 all using the cuff occlusion hyperemia paradigm. They subsequently put these MRI approaches together into a single MRI pulse sequence, combining measures of Perfusion, IntraVenous Oxygen saturation, and T2* (equivalent to bloodoxygen-level–dependent) or PIVOT that was piloted in healthy controls during cuff occlusion and hyperemia.19 PIVOT has a temporal resolution of 2 seconds and thus can measure the kinetics of perfusion, venous oxygenation, and T2*. In this study, the authors studied 96 patients with PAD with a broad range of ABI and 10 healthy controls with PIVOT. Peak values for perfusion were all lower and time to peak perfusion and T2* longer in PAD than controls. Increases in time to peak for all 3 measures correlated inversely to the ABI. However, peak perfusion values did not correspond to the ABI, which is not surprising because the ABI measures bulk arterial flow and does not take collateral flow into account. The authors demonstrate that the most reliable measures were time to peak perfusion and time to peak T2*. PIVOT is an elegant technique and was carefully studied. The question remains, is it practical and useful for clinical trials? One of the strengths and, consequently, drawbacks of MRI is its technological versatility. Physicists and engineers
See Article by Englund et al To fill this void, several investigative groups have been recently developing novel magnetic resonance imaging (MRI) and magnetic resonance spectroscopic techniques aimed for use in clinical trials. 31Phosphorus magnetic resonance spectroscopy can be used to measure phosphocreatine recovery kinetics in the calf musculature at end exercise as a sensitive marker of ischemia9 and it correlates with treadmill walking time10 and as such may be used as a surrogate marker. However, 31 P magnetic resonance spectroscopy is not widely available which limits its potential use. First-pass contrast-enhanced MRI at peak exercise can be applied to quantify a semiquantitative calf muscle perfusion index normalized to the arterial input function11 and it correlates with 6-minute walk distance.10
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Departments of Medicine and Radiology, University of Virginia Health System, Charlottesville. Correspondence to Christopher M. Kramer, MD, Cardiovascular Imaging Center, University of Virginia Health System, Lee St, Box 800170, Charlottesville, VA 22908. E-mail [email protected] (Circ Cardiovasc Imaging. 2015;8:e003360. DOI: 10.1161/CIRCIMAGING.115.003360.) © 2015 American Heart Association, Inc. irc Cardiovasc Imaging is available at C http://circimaging.ahajournals.org DOI: 10.1161/CIRCIMAGING.115.003360
1
2 Kramer Novel MRI Endpoints in PAD can constantly develop exciting new pulse sequences that enable characterization of physiology in a myriad of ways. At times, innovation gets in the way of practicality. If the field is trying to develop techniques for use in clinical trials that can be implemented in a multicenter fashion and on scanners from different vendors, then simpler approaches using 1 reproducible technique may be more practical. The other question that must be raised, are 3 measures truly better than 1? The venous blood oxygenation measure may not stand the test of time as it was only able to be measured in 77% of cases and was the least reproducible of the 3. In addition, one must ask whether time to peak perfusion is really measuring different physiology than time to peak T2*? Peak perfusion was measured in different muscle groups, whereas T2* was measured through the entire calf. Neither end point was correlated with walking performance in this study, so we do not know whether 1 is more physiologically meaningful than the other. In addition, the reproducibility of both measures, especially in patients with PAD, was modest and inferior to absolute peak ASL perfusion measures recently published.15 The authors suggest that the changes between time points in the same individual may be measuring clinically relevant changes, but 3 months is a relatively short-time frame for physiology of PAD to change significantly without an interval intervention. If one was designing a clinical trial and performing power analyses to minimize the n to study in each group, the most reproducible measure would be the most attractive. As the authors point out, the PIVOT measures may be best for measuring differences between groups, but perhaps not in a patient over time or with a particular intervention. PAD is stepwise becoming a more robustly studied atherosclerotic vascular disease. The number of potential therapeutic interventions is steadily growing as is the number of potential surrogate end points for clinical trials for these interventions. The next step must be multicenter implementation of the techniques that are deemed most useful, practical, and reproducible. Only then will the field of testing these interventions fully mature. In the meantime, exciting novel approaches continue to develop, aimed at improved the understanding of the pathophysiology of PAD and serving as a window into atherosclerosis and its downstream effects.
Disclosures Dr Kramer is supported by R01 HL075792 and U01HL117006-01A1 and receives research equipment support from Siemens Healthcare.
References 1. Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, Norman PE, Sampson UK, Williams LJ, Mensah GA, Criqui MH. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet. 2013;382:1329–1340. doi: 10.1016/S0140-6736(13)61249-0. 2. Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, Findeiss LK, Golzarian J, Gornik HL, Halperin JL, Jaff MR, Moneta GL, Olin JW, Stanley JC, White CJ, White JV, Zierler RE; Society for Cardiovascular Angiography and Interventions; Society of Interventional Radiology; Society for Vascular Medicine; Society for Vascular Surgery. 2011 ACCF/ AHA Focused Update of the Guideline for the Management of Patients With Peripheral Artery Disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart
Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011;58:2020–2045. doi: 10.1016/j.jacc.2011.08.023. 3. Murphy TP, Cutlip DE, Regensteiner JG, Mohler ER III, Cohen DJ, Reynolds MR, Massaro JM, Lewis BA, Cerezo J, Oldenburg NC, Thum CC, Jaff MR, Comerota AJ, Steffes MW, Abrahamsen IH, Goldberg S, Hirsch AT. Supervised exercise, stent revascularization, or medical therapy for claudication due to aortoiliac peripheral artery disease: the CLEVER study. J Am Coll Cardiol. 2015;65:999–1009. doi: 10.1016/j. jacc.2014.12.043. 4. Poole J, Mavromatis K, Binongo JN, Khan A, Li Q, Khayata M, Rocco E, Topel M, Zhang X, Brown C, Corriere MA, Murrow J, Sher S, Clement S, Ashraf K, Rashed A, Kabbany T, Neuman R, Morris A, Ali A, Hayek S, Oshinski J, Yoon YS, Waller EK, Quyyumi AA. Effect of progenitor cell mobilization with granulocyte-macrophage colony-stimulating factor in patients with peripheral artery disease: a randomized clinical trial. JAMA. 2013;310:2631–2639. doi: 10.1001/jama.2013.282540. 5. Annex BH. Therapeutic angiogenesis for critical limb ischaemia. Nat Rev Cardiol. 2013;10:387–396. doi: 10.1038/nrcardio.2013.70. 6. Aboyans V, Criqui MH, Abraham P, Allison MA, Creager MA, Diehm C, Fowkes FG, Hiatt WR, Jönsson B, Lacroix P, Marin B, McDermott MM, Norgren L, Pande RL, Preux PM, Stoffers HE, Treat-Jacobson D; American Heart Association Council on Peripheral Vascular Disease; Council on Epidemiology and Prevention; Council on Clinical Cardiology; Council on Cardiovascular Nursing; Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery and Anesthesia. Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association. Circulation. 2012;126:2890–2909. doi: 10.1161/CIR.0b013e318276fbcb. 7. McDermott MM, Guralnik JM, Criqui MH, Liu K, Kibbe MR, Ferrucci L. Six-minute walk is a better outcome measure than treadmill walking tests in therapeutic trials of patients with peripheral artery disease. Circulation. 2014;130:61–68. doi: 10.1161/CIRCULATIONAHA.114.007002. 8. Hiatt WR, Rogers RK, Brass EP. The treadmill is a better functional test than the 6-minute walk test in therapeutic trials of patients with peripheral artery disease. Circulation. 2014;130:69–78. doi: 10.1161/ CIRCULATIONAHA.113.007003. 9. Isbell DC, Berr SS, Toledano AY, Epstein FH, Meyer CH, Rogers WJ, Harthun NL, Hagspiel KD, Weltman A, Kramer CM. Delayed calf muscle phosphocreatine recovery after exercise identifies peripheral arterial disease. J Am Coll Cardiol. 2006;47:2289–2295. doi: 10.1016/j. jacc.2005.12.069. 10. Anderson JD, Epstein FH, Meyer CH, Hagspiel KD, Wang H, Berr SS, Harthun NL, Weltman A, Dimaria JM, West AM, Kramer CM. Multifactorial determinants of functional capacity in peripheral arterial disease: uncoupling of calf muscle perfusion and metabolism. J Am Coll Cardiol. 2009;54:628–635. doi: 10.1016/j.jacc.2009.01.080. 11. Isbell DC, Epstein FH, Zhong X, DiMaria JM, Berr SS, Meyer CH, Rogers WJ, Harthun NL, Hagspiel KD, Weltman A, Kramer CM. Calf muscle perfusion at peak exercise in peripheral arterial disease: measurement by first-pass contrast-enhanced magnetic resonance imaging. J Magn Reson Imaging. 2007;25:1013–1020. doi: 10.1002/jmri.20899. 12. Williams DS, Detre JA, Leigh JS, Koretsky AP. Magnetic resonance imaging of perfusion using spin inversion of arterial water. Proc Natl Acad Sci U S A. 1992;89:212–216. 13. Wu WC, Mohler E III, Ratcliffe SJ, Wehrli FW, Detre JA, Floyd TF. Skeletal muscle microvascular flow in progressive peripheral artery disease: assessment with continuous arterial spin-labeling perfusion magnetic resonance imaging. J Am Coll Cardiol. 2009;53:2372–2377. doi: 10.1016/j.jacc.2009.03.033. 14. Pollak AW, Meyer CH, Epstein FH, Jiji RS, Hunter JR, Dimaria JM, Christopher JM, Kramer CM. Arterial spin labeling MR imaging reproducibly measures peak-exercise calf muscle perfusion: a study in patients with peripheral arterial disease and healthy volunteers. JACC Cardiovasc Imaging. 2012;5:1224–1230. doi: 10.1016/j.jcmg.2012.03.022. 15. Lopez D, Pollak AW, Meyer CH, Epstein FH, Pesch AJ, Jiji RS, Kay JR, Dimaria JM, Christopher JM, Kramer CM. Arterial spin labeling calf perfusion CMR in peripheral arterial disease: cuff occlusion hyperemia vs. exercise. J Cardiovasc Magn Reson. 2015;17:23. doi:10.1186/s12968-015-0128-y. 16. Ledermann HP, Schulte AC, Heidecker HG, Aschwanden M, Jäger KA, Scheffler K, Steinbrich W, Bilecen D. Blood oxygenation level-dependent magnetic resonance imaging of the skeletal muscle in patients with peripheral arterial occlusive disease. Circulation. 2006;113:2929–2935. doi: 10.1161/CIRCULATIONAHA.105.605717. 17. Englund EK, Langham MC, Ratcliffe SJ, Fanning MJ, Wehrli FW, Mohler ER III, Floyd TF. Multiparametric assessment of vascular function in periph-
3 Kramer Novel MRI Endpoints in PAD eral artery disease: dynamic measurement of skeletal muscle perfusion, bloodoxygen-level dependent signal, and venous oxygen saturation. Circ Cardiovasc Imaging. 2015;8:e002673. doi: 10.1161/CIRCIMAGING.114.002673. 18. Langham MC, Floyd TF, Mohler ER III, Magland JF, Wehrli FW. Evaluation of cuff-induced ischemia in the lower extremity by magnetic resonance oximetry. J Am Coll Cardiol. 2010;55:598–606. doi: 10.1016/j. jacc.2009.08.068.
19. Englund EK, Langham MC, Li C, Rodgers ZB, Floyd TF, Mohler ER, Wehrli FW. Combined measurement of perfusion, venous oxygen saturation, and skeletal muscle T2* during reactive hyperemia in the leg. J Cardiovasc Magn Reson. 2013;15:70. doi: 10.1186/1532-429X-15-70. Key Words: Editorials ◼ magnetic resonance imaging ◼ perfusion ◼ peripheral arterial disease ◼ peripheral vascular diseases
Novel Magnetic Resonance Imaging End Points for Physiologic Studies in Peripheral Arterial Disease: Elegance Versus Practicality Christopher M. Kramer Circ Cardiovasc Imaging. 2015;8: doi: 10.1161/CIRCIMAGING.115.003360 Circulation: Cardiovascular Imaging is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 1941-9651. Online ISSN: 1942-0080
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circimaging.ahajournals.org/content/8/4/e003360
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation: Cardiovascular Imaging can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation: Cardiovascular Imaging is online at: http://circimaging.ahajournals.org//subscriptions/
