Coronary microvascular dysfunction: Mechanisms and functional assessment

Nature Reviews Cardiology

Volumn 12, Issue 1, 2015, Pages 48-62

  Camici, Paolo G ^a   D'Amati, Giulia ^b   Rimoldi, Ornella ^c  

^a VITA SALUTE SAN RAFFAELE UNIVERSITY   (Italy)

^b SAPIENZA UNIVERSITY OF ROME   (Italy)

^c CNR   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ACUTE HEART INFARCTION; ANGINA PECTORIS; AORTA STENOSIS; BLOOD FLOW VELOCITY; CARDIOVASCULAR DISEASE; CARDIOVASCULAR MAGNETIC RESONANCE; CARDIOVASCULAR PROCEDURE; CARDIOVASCULAR RISK; CORONARY ARTERY BLOOD FLOW; CORONARY ARTERY OBSTRUCTION; CORONARY FLOW RESERVE; CORONARY MICROVASCULAR DYSFUNCTION; DOPPLER ECHOCARDIOGRAPHY; DYSLIPIDEMIA; FUNCTIONAL ASSESSMENT; HEART CATHETERIZATION; HEART LEFT VENTRICLE HYPERTROPHY; HEART MUSCLE ISCHEMIA; HUMAN; HYPERTROPHIC CARDIOMYOPATHY; INVASIVE PROCEDURE; MICROCIRCULATION; NON INSULIN DEPENDENT DIABETES MELLITUS; NON INVASIVE PROCEDURE; POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; PROGNOSIS; REPERFUSION INJURY; REVIEW; SMOKING; TRANSTHORACIC ECHOCARDIOGRAPHY; COMPUTER ASSISTED TOMOGRAPHY; CORONARY BLOOD VESSEL; NUCLEAR MAGNETIC RESONANCE IMAGING; PATHOPHYSIOLOGY; PHYSIOLOGY; PROCEDURES;

BLOOD FLOW VELOCITY; CORONARY CIRCULATION; CORONARY VESSELS; ECHOCARDIOGRAPHY, DOPPLER; HUMANS; MAGNETIC RESONANCE IMAGING; MICROCIRCULATION; POSITRON-EMISSION TOMOGRAPHY; TOMOGRAPHY, X-RAY COMPUTED;

EID: 84927570395     PISSN: 17595002     EISSN: 17595010     Source Type: Journal    
DOI: 10.1038/nrcardio.2014.160     Document Type: Review

References (169)

1. Crea, F., Lanza, G. A. & Camici, P. G. Coronary Microvascular Dysfunction (Springer Verlag, 2014).
2. Camici, P. G., Olivotto, I. & Rimoldi, O. E. The coronary circulation and blood flow in left ventricular hypertrophy. J. Mol. Cell. Cardiol. 52, 857-864 (2012).
3. Camici, P. G. & Crea, F. Coronary microvascular dysfunction. N. Engl. J. Med. 356, 830-840 (2007).
4. Murthy, V. L. et al. Effects of sex on coronary microvascular dysfunction and cardiac outcomes. Circulation 129, 2518-2527 (2014).
5. Crea, F., Camici, P. G. & Bairey Merz, C. N. Coronary microvascular dysfunction: an update. Eur. Heart J. 35, 1101-1111 (2013).
6. Tanaka, M. et al. Quantitative analysis of narrowings of intramyocardial small arteries in normal hearts, hypertensive hearts, and hearts with hypertrophic cardiomyopathy. Circulation 75, 1130-1139 (1987).
7. Duncker, D. J. & Bache, R. J. Regulation of coronary blood flow during exercise. Physiol. Rev. 88, 1009-1086 (2008).
8. Clarke, J. G. et al. Coronary artery infusion of neuropeptide Y in patients with angina pectoris. Lancet 1, 1057-1059 (1987).
9. Ong, P. et al. Increased coronary vasoconstrictor response to acetylcholine in women with chest pain and normal coronary arteriograms (cardiac syndrome X). Clin. Res. Cardiol. 101, 673-681 (2012).
10. Matsuda, K. et al. Response of the left anterior descending coronary artery to acetylcholine in patients with chest pain and angiographically normal coronary arteries. Am. J. Cardiol. 92, 1394-1398 (2003).
11. Gould, K. L. et al. Anatomic versus physiologic assessment of coronary artery disease. Role of coronary flow reserve, fractional flow reserve, and positron emission tomography imaging in revascularization decision-making. J. Am. Coll. Cardiol. 62, 1639-1653 (2013).
12. Inoue, K. et al. Myocardial microvascular abnormalities observed by intravenous myocardial contrast echocardiography in patients with hypertrophic cardiomyopathy. Am. J. Cardiol. 94, 55-58 (2004).
13. Choudhury, L., Rosen, S. D., Patel, D., Nihoyannopoulos, P. & Camici, P. G. Coronary vasodilator reserve in primary and secondary left ventricular hypertrophy. A study with positron emission tomography. Eur. Heart J. 18, 108-116 (1997).
14. Downey, J. M. in Physiology and Pathophysiology of the Heart (ed. Sperelakis, N.) 1109-1123 (Kluwer, 1995).
15. Chareonthaitawee, P., Kaufmann, P. A., Rimoldi, O. & Camici, P. G. Heterogeneity of resting and hyperemic myocardial blood flow in healthy humans. Cardiovasc. Res. 50, 151-161 (2001).
16. Cortigiani, L. et al. Prognostic effect of coronary flow reserve in women versus men with chest pain syndrome and normal dipyridamole stress echocardiography. Am. J. Cardiol. 106, 1703-1708 (2010).
17. Rosen, S D. et Al. Coronary Vasodilator Reserve, Pain Perception, and Sex in Patients with Syndrome X. Circulation 90, 50-60 (1994).
18. Renaud, J. M., DaSilva, J. N., Beanlands, R. S. & DeKemp, R. A. Characterizing the normal range of myocardial blood flow with 82rubidium and 13N-Ammonia PET imaging. J. Nucl. Cardiol. 20, 578-591 (2013).
19. Layland, J., Carrick, D., Lee, M., Oldroyd, K. & Berry, C. Adenosine: physiology, pharmacology, and clinical applications. JACC Cardiovasc. Interv. 7, 581-591 (2014).
20. Jagathesan, R., Barnes, E., Rosen, S. D., Foale, R. A. & Camici, P. G. Comparison of myocardial blood flow and coronary flow reserve during dobutamine and adenosine stress: Implications for pharmacologic stress testing in coronary artery disease. J. Nucl. Cardiol. 13, 324-332 (2006).
21. Heusch, G. Adenosine and maximum coronary vasodilation in humans: myth and misconceptions in the assessment of coronary reserve. Basic Res. Cardiol. 105, 1-5 (2010).
22. Camici, P. G. Absolute figures are better than percentages. JACC Cardiovasc. Imaging 2, 759-760 (2009).
23. Quinones, M. J. et al. Coronary vasomotor abnormalities in insulin-resistant individuals. Ann. Intern. Med. 140, 700-708 (2004).
24. Schindler, T. H. et al. PET-measured responses of MBF to cold pressor testing correlate with indices of coronary vasomotion on quantitative coronary angiography. J. Nucl. Med. 45, 419-428 (2004).
25. Meimoun, P. et al. Transthoracic coronary flow velocity reserve assessment: comparison between adenosine and dobutamine. J. Am. Soc. Echocardiogr. 19, 1220-1228 (2006).
26. Caiati, C. et al. Validation of a new noninvasive method (contrast-enhanced transthoracic second harmonic echo Doppler) for the evaluation of coronary flow reserve: comparison with intracoronary Doppler flow wire. J. Am. Coll. Cardiol. 34, 1193-1200 (1999).
27. Hozumi, T. et al. Noninvasive assessment of coronary flow velocity and coronary flow velocity reserve in the left anterior descending coronary artery by Doppler echocardiography: comparison with invasive technique. J. Am. Coll. Cardiol. 32, 1251-1259 (1998).
28. Lethen, H., Tries, H. P., Kersting, S. & Lambertz, H. Validation of noninvasive assessment of coronary flow velocity reserve in the right coronary artery. A comparison of transthoracic echocardiographic results with intracoronary Doppler flow wire measurements. Eur. Heart J. 24, 1567-1575 (2003).
29. Caiati, C., Zedda, N., Montaldo, C., Montisci, R. & Iliceto, S. Contrast-enhanced transthoracic second harmonic echo Doppler with adenosine: a noninvasive, rapid and effective method for coronary flow reserve assessment. J. Am. Coll. Cardiol. 34, 122-130 (1999).
30. Takeuchi, M. et al. Measurement of coronary flow velocity reserve in the posterior descending coronary artery by contrast-enhanced transthoracic Doppler echocardiography. J. Am. Soc. Echocardiogr. 17, 21-27 (2004).
31. Meimoun, P. & Tribouilloy, C. Non-invasive assessment of coronary flow and coronary flow reserve by transthoracic Doppler echocardiography: a magic tool for the real world. Eur. J. Echocardiogr. 9, 449-457 (2008).
32. Cortigiani, L. et al. Implication of the continuous prognostic spectrum of Doppler echocardiographic derived coronary flow reserve on left anterior descending artery. Am. J. Cardiol. 105, 158-162 (2010).
33. Sicari, R. et al. Additive prognostic value of coronary flow reserve in patients with chest pain syndrome and normal or near-normal coronary arteries. Am. J. Cardiol. 103, 626-631 (2009).
34. Rigo, F. et al. Usefulness of coronary flow reserve over regional wall motion when added to dual-imaging dipyridamole echocardiography. Am. J. Cardiol. 91, 269-273 (2003).
35. Kaul, S. Myocardial contrast echocardiography: 15 years of research and development. Circulation 96, 3745-3760 (1997).
36. Kaul, S. Myocardial contrast echocardiography: a 25-year retrospective. Circulation 118, 291-308 (2008).
37. Porter, T. R. & Xie, F. Myocardial perfusion imaging with contrast ultrasound. JACC Cardiovasc. Imaging 3, 176-187 (2010).
38. Wei, K. et al. Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. Circulation 97, 473-483 (1998).
39. Vogel, R. et al. The quantification of absolute myocardial perfusion in humans by contrast echocardiography: algorithm and validation. J. Am. Coll. Cardiol. 45, 754-762 (2005).
40. Exuzides, A. et al. A retrospective comparison of mortality in critically ill hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent. JACC Cardiovasc. Imaging 3, 578-585 (2010).
41. Lepper, W. et al. Assessment of myocardial reperfusion by intravenous myocardial contrast echocardiography and coronary flow reserve after primary percutaneous transluminal coronary angioplasty [correction of angiography] in patients with acute myocardial infarction. Circulation 101, 2368-2374 (2000).
42. Dwivedi, G., Janardhanan, R., Hayat, S. A., Swinburn, J. M. & Senior, R. Prognostic value of myocardial viability detected by myocardial contrast echocardiography early after acute myocardial infarction. J. Am. Coll. Cardiol. 50, 327-334 (2007).
43. Galiuto, L. et al. The extent of microvascular damage during myocardial contrast echocardiography is superior to other known indexes of post-infarct reperfusion in predicting left ventricular remodeling: results of the multicenter AMICI study. J. Am. Coll. Cardiol. 51, 552-559 (2008).
44. Gaibazzi, N., Reverberi, C., Lorenzoni, V., Molinaro, S. & Porter, T. R. Prognostic value of high-dose dipyridamole stress myocardial contrast perfusion echocardiography. Circulation 126, 1217-1224 (2012).
45. Gurudevan, S. V. et al. Cocaine-induced vasoconstriction in the human coronary microcirculation: new evidence from myocardial contrast echocardiography. Circulation 128, 598-604 (2013).
46. Nef, H. M., Mollmann, H., Akashi, Y. J. & Hamm, C. W. Mechanisms of stress (Takotsubo) cardiomyopathy. Nat. Rev. Cardiol. 7, 187-193 (2010).
47. Galiuto, L. et al. Reversible coronary microvascular dysfunction: a common pathogenetic mechanism in apical ballooning or Tako-Tsubo syndrome. Eur. Heart J. 31, 1319-1327 (2010).
48. Camici, P. G. & Rimoldi, O. E. The clinical value of myocardial blood flow measurement. J. Nucl. Med. 50, 1076-1087 (2009).
49. Schaefers, K. et al. Absolute quantification of myocardial blood flow with H215O and 3 dimensional PET: an experimental validation. J. Nucl. Med. 43, 1031-1040 (2002).
50. Schepis, T. et al. Absolute quantification of myocardial blood flow with 13N-Ammonia and 3 dimensional PET. J. Nucl. Med. 48, 1783-1789 (2007).
51. Kaufmann, P. A. et al. Coronary heart disease in smokers: vitamin C restores coronary microcirculatory function. Circulation 102, 1233-1238 (2000).
52. Kaufmann, P. A., Gnecchi-Ruscone, T., Schafers, K. P., Luscher, T. F. & Camici, P. G. Low density lipoprotein cholesterol and coronary microvascular dysfunction in hypercholesterolemia. J. Am. Coll. Cardiol. 36, 103-109 (2000).
53. Di Carli, M. F. et al. Coronary circulatory function in patients with the metabolic syndrome. J. Nucl. Med. 52, 1369-1377 (2011).
54. Danad, I. et al. Coronary risk factors and myocardial blood flow in patients evaluated for coronary artery disease: a quantitative [15O]H2O PET/CT study. Eur. J. Nucl. Med. Mol. Imaging 39, 102-112 (2012).
55. Recio-Mayoral, A., Rimoldi, O. E., Camici, P. G. & Kaski, J. C. Inflammation and microvascular dysfunction in cardiac syndrome x patients without conventional risk factors for coronary artery disease. JACC Cardiovasc. Imaging 6, 660-667 (2013).
56. Schindler, T. H. et al. Improvement in coronary vascular dysfunction produced with euglycaemic control in patients with type 2 diabetes. Heart 93, 345-349 (2007).
57. Schindler, T. H. et al. Relationship between increasing body weight, insulin resistance, inflammation, adipocytokine leptin, and coronary circulatory function. J. Am. Coll. Cardiol. 47, 1188-1195 (2006).
58. Neglia, D. et al. Perindopril and indapamide reverse coronary microvascular remodelling and improve flow in arterial hypertension. J. Hypertens. 29, 364-372 (2011).
59. Prior, J. O. et al. Coronary circulatory dysfunction in insulin resistance, impaired glucose tolerance, and type 2 diabetes mellitus. Circulation 111, 2291-2298 (2005).
60. Buus, N. H. et al. Myocardial perfusion during long-Term angiotensin-converting enzyme inhibition or beta-blockade in patients with essential hypertension. Hypertension 44, 465-470 (2004).
61. Akinboboye, O. O., Chou, R. L. & Bergmann, S. R. Augmentation of myocardial blood flow in hypertensive heart disease by angiotensin antagonists: a comparison of lisinopril and losartan. J. Am. Coll. Cardiol. 40, 703-709 (2002).
62. Higuchi, T., Abletshauser, C., Nekolla, S. G., Schwaiger, M. & Bengel, F. M. Effect of the angiotensin receptor blocker valsartan on coronary microvascular flow reserve in moderately hypertensive patients with stable coronary artery disease. Microcirculation 14, 805-812 (2007).
63. Iozzo, P. et al. Mismatch between insulin-mediated glucose uptake and blood flow in the heart of patients with type II diabetes. Diabetologia 45, 1404-1409 (2002).
64. Momose, M. et al. Dysregulation of coronary microvascular reactivity in asymptomatic patients with type 2 diabetes mellitus. Eur. J. Nucl. Med. Mol. Imaging 29, 1675-1679 (2002).
65. Yokoyama, I. et al. Coronary microangiopathy in type 2 diabetic patients: relation to glycemic control, sex, and microvascular angina rather than to coronary artery disease. J. Nucl. Med. 41, 978-985 (2000).
66. Nahser P. J. Jr, Brown, R. E., Oskarsson, H., Winniford, M. D. & Rossen, J. D. Maximal coronary flow reserve and metabolic coronary vasodilation in patients with diabetes mellitus. Circulation 91, 635-640 (1995).
67. Murthy, V. L. et al. Association between coronary vascular dysfunction and cardiac mortality in patients with and without diabetes mellitus. Circulation 126, 1858-1868 (2012).
68. Lautamaki, R. et al. Insulin improves myocardial blood flow in patients with type 2 diabetes and coronary artery disease. Diabetes 55, 511-516 (2006).
69. Yokoyama, I. et al. Reduced coronary flow reserve in hypercholesterolemic patients without overt coronary stenosis. Circulation 94, 3232-3238 (1996).
70. Guethlin, M. et al. Delayed response of myocardial flow reserve to lipid-lowering therapy with fluvastatin. Circulation 99, 475-481 (1999).
71. Naoumova, R. P. et al. Pioglitazone improves myocardial blood flow and glucose utilization in nondiabetic patients with combined hyperlipidemia: a randomized, double-blind, placebo-controlled study. J. Am. Coll. Cardiol. 50, 2051-2058 (2007).
72. Gaemperli, O., Liga, R., Bhamra-Ariza, P. & Rimoldi, O. Nicotine addiction and coronary artery disease: impact of cessation interventions. Curr. Pharm. Des. 16, 2586-2597 (2010).
73. Campisi, R. et al. Effects of long-Term smoking on myocardial blood flow, coronary vasomotion, and vasodilator capacity. Circulation 98, 119-125 (1998).
74. Iwado, Y. et al. Decreased endothelium-dependent coronary vasomotion in healthy young smokers. Eur. J. Nucl. Med. Mol. Imaging 29, 984-990 (2002).
75. Rooks, C. et al. Effects of smoking on coronary microcirculatory function: a twin study. Atherosclerosis 215, 500-506 (2011).
76. Rajappan, K. et al. Mechanisms of coronary microcirculatory dysfunction in patients with aortic stenosis and angiographically normal coronary arteries. Circulation 105, 470-476 (2002).
77. Akinboboye, O. O. et al. Positron emission tomography, echo-doppler, and exercise studies of functional capacity in hypertensive heart disease. Am. J. Hypertens. 15, 907-910 (2002).
78. Choudhury, L. et al. Transmural myocardial blood flow distribution in hypertrophic cardiomyopathy and effect of treatment. Basic Res. Cardiol. 94, 49-59 (1999).
79. Knaapen, P. et al. Determinants of coronary microvascular dysfunction in symptomatic hypertrophic cardiomyopathy. Am. J. Physiol. Heart Circ. Physiol. 294, H986-H993 (2008).
80. Timmer, S. A. et al. Effects of alcohol septal ablation on coronary microvascular function and myocardial energetics in hypertrophic obstructive cardiomyopathy. Am. J. Physiol. Heart Circ. Physiol. 301, H129-H137 (2011).
81. Cecchi, F. et al. Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. N. Engl. J. Med. 349, 1027-1035 (2003).
82. Olivotto, I. et al. Relevance of coronary microvascular flow impairment to long-Term remodeling and systolic dysfunction in hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 47, 1043-1048 (2006).
83. Maron, M. S. et al. The case for myocardial ischemia in hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 54, 866-875 (2009).
84. Carabello, B. A. Clinical practice. Aortic stenosis. N. Engl. J. Med. 346, 677-682 (2002).
85. Garcia, D. et al. Impairment of coronary flow reserve in aortic stenosis. J. Appl. Physiol. 106, 113-121 (2009).
86. Uren, N. G., Marraccini, P., Gistri, R., de Silva, R. & Camici, P. G. Altered coronary vasodilator reserve and metabolism in myocardium subtended by normal arteries in patients with coronary artery disease. J. Am. Coll. Cardiol. 22, 650-658 (1993).
87. Herzog, B. A. et al. Long-Term prognostic value of 13N-Ammonia myocardial perfusion positron emission tomography added value of coronary flow reserve. J. Am. Coll. Cardiol. 54, 150-156 (2009).
88. Murthy, V. L. et al. Improved cardiac risk assessment with noninvasive measures of coronary flow reserve. Circulation 124, 2215-2224 (2011).
89. Fukushima, K. et al. Prediction of short-Term cardiovascular events using quantification of global myocardial flow reserve in patients referred for clinical 82Rb PET perfusion imaging. J. Nucl. Med. 52, 726-732 (2011).
90. Ziadi, M. C. et al. Impaired myocardial flow reserve on rubidium 82 positron emission tomography imaging predicts adverse outcomes in patients assessed for myocardial ischemia. J. Am. Coll. Cardiol. 58, 740-748 (2011).
91. Neglia, D. et al. Prognostic role of myocardial blood flow impairment in idiopathic left ventricular dysfunction. Circulation 105, 186-193 (2002).
92. Tong, C. Y. et al. Measurement of the extraction efficiency and distribution volume for Gd-DTPA in normal and diseased canine myocardium. Magn. Reson. Med. 30, 337-346 (1993).
93. Klem, I. et al. Improved detection of coronary artery disease by stress perfusion cardiovascular magnetic resonance with the use of delayed enhancement infarction imaging. J. Am. Coll. Cardiol. 47, 1630-1638 (2006).
94. Ingkanisorn, W. P. et al. Prognosis of negative adenosine stress magnetic resonance in patients presenting to an emergency department with chest pain. J. Am. Coll. Cardiol. 47, 1427-1432 (2006).
95. Christian, T., Aletras, A. H. & Arai, A. E. Estimation of absolute myocardial blood flow during first-pass MR perfusion imaging using a dual-bolus injection technique: comparison to single-bolus injection method. J. Magn. Reson. Imaging 27, 1271-1277 (2008).
96. Goldstein, T. A. et al. Fast mapping of myocardial blood flow with MR first-pass perfusion imaging. Magn. Reson. Med. 59, 1394-1400 (2008).
97. Lee, D. C. et al. Magnetic resonance versus radionuclide pharmacological stress perfusion imaging for flow-limiting stenoses of varying severity. Circulation 110, 58-65 (2004).
98. Hsu, L. Y. et al. Quantitative myocardial perfusion analysis with a dual-bolus contrast-enhanced first-pass MRI technique in humans. J. Magn. Reson. Imaging 23, 315-322 (2006).
99. Köstler, H. et al. Comparison of different contrast agents and doses for quantitative MR myocardial perfusion imaging. J. Magn. Reson. Imaging 28, 382-389 (2008).
100. Cheng, A. S. et al. Cardiovascular magnetic resonance perfusion imaging at 3 tesla for the detection of coronary artery disease: a comparison with 1.5-Tesla. J. Am. Coll. Cardiol. 49, 2440-2449 (2007).
101. Petersen, S. E. et al. Evidence for microvascular dysfunction in hypertrophic cardiomyopathy: new insights from multiparametric magnetic resonance imaging. Circulation 115, 2418-2425 (2007).
102. Schwitter, J. et al. Assessment of myocardial perfusion in coronary artery disease by magnetic resonance: a comparison with positron emission tomography and coronary angiography. Circulation 103, 2230-2235 (2001).
103. Rosen, B. D. et al. Lower myocardial perfusion reserve is associated with decreased regional left ventricular function in asymptomatic participants of the multi-ethnic study of atherosclerosis. Circulation 114, 289-297 (2006).
104. Motwani, M., Jogiya, R., Kozerke, S., Greenwood, J. P. & Plein, S. Advanced cardiovascular magnetic resonance myocardial perfusion imaging: high-spatial resolution versus 3 dimensional whole-heart coverage. Circ. Cardiovasc. Imaging 6, 339-348 (2013).
105. Coelho-Filho, O. R., Rickers, C., Kwong, R. Y. & Jerosch-Herold, M. MR myocardial perfusion imaging. Radiology 266, 701-715 (2013).
106. Greenwood, J P. et Al. Comparison of Cardiovascular Magnetic Resonance and Single-photon Emission Computed Tomography in Women with Suspected Coronary Artery Disease from the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease (CE-MARC) Trial. Circulation 129, 1129-1138 (2014).
107. Schwitter, J. et al. MR IMPACT II: Magnetic Resonance Imaging for Myocardial Perfusion Assessment in Coronary Artery Disease Trial: perfusion-cardiac magnetic resonance vs. single photon emission computed tomography for the detection of coronary artery disease: a comparative multicentre, multivendor trial. Eur. Heart J. 34, 775-781 (2013).
108. Al-Saadi, N. et al. Noninvasive detection of myocardial ischemia from perfusion reserve based on cardiovascular magnetic resonance. Circulation 101, 1379-1383 (2000).
109. Jerosch-Herold, M., Swingen, C. & Seethamraju, R. T. Myocardial blood flow quantification with MRI by model-independent deconvolution. Med. Phys. 29, 886-897 (2002).
110. Motwani, M. et al. Quantitative three-dimensional cardiovascular magnetic resonance myocardial perfusion imaging in systole and diastole. J. Cardiovasc. Magn. Reson. 16, 19 (2014).
111. Hsu, L. Y., Kellman, P. & Arai, A. E. Nonlinear myocardial signal intensity correction improves quantification of contrast-enhanced first-pass MR perfusion in humans. J. Magn. Reson. Imaging 27, 793-801 (2008).
112. Gargiulo, P. et al. The prognostic value of normal stress cardiac magnetic resonance in patients with known or suspected coronary artery disease: a meta-Analysis. Circ. Cardiovasc. Imaging 6, 574-582 (2013).
113. Lipinski, M. J., McVey, C. M., Berger, J. S., Kramer, C. M. & Salerno, M. Prognostic value of stress cardiac magnetic resonance imaging in patients with known or suspected coronary artery disease: a systematic review and meta-Analysis. J. Am. Coll. Cardiol. 62, 826-838 (2013).
114. Wang, L., Jerosch-Herold, M., Jacobs, J. D. R., Shahar, E. & Folsom, A. R. Coronary risk factors and myocardial perfusion in asymptomatic adults: the Multi-Ethnic Study of Atherosclerosis (MESA). J. Am. Coll. Cardiol. 47, 565-572 (2006).
115. Doyle, M. et al. Prognostic value of global MR myocardial perfusion imaging in women with suspected myocardial ischemia and no obstructive coronary disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study. JACC Cardiovasc. Imaging 3, 1030-1036 (2010).
116. Karamitsos, T. D. et al. Blunted myocardial oxygenation response during vasodilator stress in patients with hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 61, 1169-1176 (2013).
117. Ito, H. No-reflow phenomenon and prognosis in patients with acute myocardial infarction. Nat. Clin. Pract. Cardiovasc. Med. 3, 499-506 (2006).
118. Bekkers, S. C., Yazdani, S. K., Virmani, R. & Waltenberger, J. Microvascular obstruction: underlying pathophysiology and clinical diagnosis. J. Am. Coll. Cardiol. 55, 1649-1660 (2010).
119. Wu, K. CMR of microvascular obstruction and hemorrhage in myocardial infarction. J. Cardiovasc. Magn. Reson. 14, 68 (2012).
120. White, S. K., Hausenloy, D. J. & Moon, J. C. Imaging the myocardial microcirculation post-myocardial infarction. Curr. Heart Fail. Rep. 9, 282-292 (2012).
121. Orn, S. et al. Microvascular obstruction is a major determinant of infarct healing and subsequent left ventricular remodelling following primary percutaneous coronary intervention. Eur. Heart J. 30, 1978-1985 (2009).
122. Mather, A. N. et al. Appearance of microvascular obstruction on high resolution first-pass perfusion, early and late gadolinium enhancement CMR in patients with acute myocardial infarction. J. Cardiovasc. Magn. Reson. 11, 33 (2009).
123. Cochet, A. A. et al. Major prognostic impact of persistent microvascular obstruction as assessed by contrast-enhanced cardiac magnetic resonance in reperfused acute myocardial infarction. Eur. Radiol. 19, 2117-2126 (2009).
124. de Waha, S. et al. Impact of early vs. late microvascular obstruction assessed by magnetic resonance imaging on long-Term outcome after ST elevation myocardial infarction: a comparison with traditional prognostic markers. Eur. Heart J. 31, 2660-2668 (2010).
125. Klug, G. et al. Prognostic value at 5 years of microvascular obstruction after acute myocardial infarction assessed by cardiovascular magnetic resonance. J. Cardiovasc. Magn. Reson. 14, 46 (2012).
126. Larose, E. et al. Predicting late myocardial recovery and outcomes in the early hours of ST segment elevation myocardial infarction traditional measures compared with microvascular obstruction, salvaged myocardium, and necrosis characteristics by cardiovascular magnetic resonance. J. Am. Coll. Cardiol. 55, 2459-2469 (2010).
127. Wu, E. et al. Infarct size by contrast enhanced cardiac magnetic resonance is a stronger predictor of outcomes than left ventricular ejection fraction or end-systolic volume index: prospective cohort study. Heart 94, 730-736 (2008).
128. Robbers, L. F. et al. Magnetic resonance imaging-defined areas of microvascular obstruction after acute myocardial infarction represent microvascular destruction and haemorrhage. Eur. Heart J. 34, 2346-2353 (2013).
129. Kidambi, A. et al. The effect of microvascular obstruction and intramyocardial hemorrhage on contractile recovery in reperfused myocardial infarction: insights from cardiovascular magnetic resonance. J. Cardiovasc. Magn. Reson. 15, 58 (2013).
130. Husser, O. et al. Cardiovascular magnetic resonance-derived intramyocardial hemorrhage after STEMI: Influence on long-Term prognosis, adverse left ventricular remodeling and relationship with microvascular obstruction. Int. J. Cardiol. 167, 2047-2054 (2013).
131. Eitel, I. et al. Prognostic value and determinants of a hypointense infarct core in T2-weighted cardiac magnetic resonance in acute reperfused ST-elevation-myocardial infarction. Circ. Cardiovasc. Imaging 4, 354-362 (2011).
132. George, R. T. et al. Quantification of myocardial perfusion using dynamic 64-detector computed tomography. Invest. Radiol. 42, 815-822 (2007).
133. Bamberg, F. et al. Dynamic myocardial CT perfusion imaging for evaluation of myocardial ischemia as determined by MR imaging. JACC Cardiovasc. Imaging 7, 267-277 (2014).
134. Taylor, C. A., Fonte, T. A. & Min, J. K. Computational fluid dynamics applied to cardiac computed tomography for noninvasive quantification of fractional flow reserve: scientific basis. J. Am. Coll. Cardiol. 61, 2233-2241 (2013).
135. Norgaard, B. L. et al. Diagnostic performance of noninvasive fractional flow reserve derived from coronary computed tomography angiography in suspected coronary artery disease: the NXT trial (analysis of coronary blood flow using CT angiography: next steps). J. Am. Coll. Cardiol. 63, 1145-1155 (2014).
136. Chesebro, J. H. et al. Thrombolysis in myocardial infarction (TIMI) trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation 76, 142-154 (1987).
137. Niccoli, G., Burzotta, F., Galiuto, L. & Crea, F. Myocardial no-reflow in humans. J. Am. Coll. Cardiol. 54, 281-292 (2009).
138. Taylor, A. et al. Detection of acutely impaired microvascular reperfusion after infarct angioplasty with magnetic resonance imaging. Circulation 109, 2080-2085 (2004).
139. Nijveldt, R. et al. Functional recovery after acute myocardial infarction: comparison between angiography, electrocardiography, and cardiovascular magnetic resonance measures of microvascular injury. J. Am. Coll. Cardiol. 52, 181-189 (2008).
140. Abaci, A., Oguzhan, A., Eryol, N. K. & Ergin, A. Effect of potential confounding factors on the Thrombolysis in Myocardial Infarction (TIMI) trial frame count and its reproducibility. Circulation 100, 2219-2223 (1999).
141. van't Hof, A. W. et al. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction: myocardial blush grade. Zwolle myocardial infarction study group. Circulation 97, 2302-2306 (1998).
142. Iwakura, K. et al. Alternation in the coronary blood flow velocity pattern in patients with no reflow and reperfused acute myocardial infarction. Circulation 94, 1269-1275 (1996).
143. Yamamoto, K. et al. Two different coronary blood flow velocity patterns in thrombolysis in myocardial infarction flow grade 2 in acute myocardial infarction: insight into mechanisms of microvascular dysfunction. J. Am. Coll. Cardiol. 40, 1755-1760 (2002).
144. Marcus, M. L., Doty, D. B., Hiratzka, L. F., Wright, C. B. & Eastham, C. L. Decreased coronary reserve: a mechanism for angina pectoris in patients with aortic stenosis and normal coronary arteries. N. Engl. J. Med. 307, 1362-1366 (1982).
145. Doucette, J. W. et al. Validation of a Doppler guide wire for intravascular measurement of coronary artery flow velocity. Circulation 85, 1899-1911 (1992).
146. Jenni, R. et al. In vitro validation of volumetric blood flow measurement using Doppler flow wire. Ultrasound Med. Biol. 26, 1301-1310 (2000).
147. Serruys, P. W. et al. Prognostic value of intracoronary flow velocity and diameter stenosis in assessing the short-And long-Term outcomes of coronary balloon angioplasty: the DEBATE Study (Doppler Endpoints Balloon Angioplasty Trial Europe). Circulation 96, 3369-3377 (1997).
148. van de Hoef, T. P. et al. Impact of coronary microvascular function on long-Term cardiac mortality in patients with acute ST segment-elevation myocardial infarction. Circ. Cardiovasc. Interv. 6, 207-215 (2013).
149. van de Hoef, T. P. et al. Physiological basis and long-Term clinical outcome of discordance between fractional flow reserve and coronary flow velocity reserve in coronary stenoses of intermediate severity. Circ. Cardiovasc. Interv. 7, 301-311 (2014).
150. Pepine, C. J. et al. Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women's Ischemia Syndrome Evaluation) study. J. Am. Coll. Cardiol. 55, 2825-2832 (2010).
151. Pauly, D. F. et al. In women with symptoms of cardiac ischemia, nonobstructive coronary arteries, and microvascular dysfunction, angiotensin-converting enzyme inhibition is associated with improved microvascular function: a double-blind randomized study from the National Heart, Lung and Blood Institute Women's Ischemia Syndrome Evaluation (WISE). Am. Heart J. 162, 678-684 (2011).
152. Meuwissen, M. et al. Hyperemic stenosis resistance index for evaluation of functional coronary lesion severity. Circulation 106, 441-446 (2002).
153. Escaned, J. et al. Assessment of microcirculatory remodeling with intracoronary flow velocity and pressure measurements: validation with endomyocardial sampling in cardiac allografts. Circulation 120, 1561-1568 (2009).
154. De Bruyne, B., Pijls, N. H., Smith, L., Wievegg, M. & Heyndrickx, G. R. Coronary thermodilution to assess flow reserve: experimental validation. Circulation 104, 2003-2006 (2001).
155. Pijls, N. H. et al. Coronary thermodilution to assess flow reserve: validation in humans. Circulation 105, 2482-2486 (2002).
156. Ng, M. K., Yeung, A. C. & Fearon, W. F. Invasive assessment of the coronary microcirculation: superior reproducibility and less hemodynamic dependence of index of microcirculatory resistance compared with coronary flow reserve. Circulation 113, 2054-2061 (2006).
157. Aarnoudse, W. et al. Epicardial stenosis severity does not affect minimal microcirculatory resistance. Circulation 110, 2137-2142 (2004).
158. Verhoeff, B. J., van de Hoef, T. P., Spaan, J. A., Piek, J. J. & Siebes, M. Minimal effect of collateral flow on coronary microvascular resistance in the presence of intermediate and noncritical coronary stenoses. Am. J. Physiol. Heart Circ. Physiol. 303, H422-H428 (2012).
159. Spaan, J. A. E., Piek, J. J., Hoffman, J. I. E. & Siebes, M. Physiological basis of clinically used coronary hemodynamic indices. Circulation 113, 446-455 (2006).
160. Duncker, D. J. & Bache, R. J. Effect of chronotropic and inotropic stimulation on the coronary pressure-flow relation in left ventricular hypertrophy. Basic Res. Cardiol. 92, 271-286 (1997).
161. Fearon, W. F. et al. Prognostic value of the index of microcirculatory resistance measured after primary percutaneous coronary intervention. Circulation 127, 2436-2441 (2013).
162. Ng, M. K. et al. The index of microcirculatory resistance predicts myocardial infarction related to percutaneous coronary intervention. Circ. Cardiovasc. Interv. 5, 515-522 (2012).
163. Cuisset, T. et al. Direct stenting for stable angina pectoris is associated with reduced periprocedural microcirculatory injury compared with stenting after pre-dilation. J. Am. Coll. Cardiol. 51, 1060-1065 (2008).
164. Mangiacapra, F. et al. Intracoronary enalaprilat to reduce MICROvascular damage during percutaneous coronary intervention (ProMicro) study. J. Am. Coll. Cardiol. 61, 615-621 (2013).
165. Bergmann, S. R. et al. Quantification of regional myocardial blood flow in vivo with H215O. Circulation 70, 724-733 (1984).
166. Bergmann, S. R., Hack, S., Tewson, T., Welch, M. J. & Sobel, B. E. The dependence of accumulation of 13NH3 by myocardium on metabolic factors and its implications for quantitative assessment of perfusion. Circulation 61, 34-43 (1980).
167. Senthamizhchelvan, S. et al. Human biodistribution and radiation dosimetry of 82Rb. J. Nucl. Med. 51, 1592-1599 (2010).
168. Berman, D. S. et al. Phase II safety and clinical comparison with single-photon emission computed tomography myocardial perfusion imaging for detection of coronary artery disease: flurpiridaz F 18 positron emission tomography. J. Am. Coll. Cardiol. 61, 469-477 (2013).
169. Bailey, D. L., Townsend, D. W., Valk, P. E. & Maisey, M. N. (Eds) Positron Emission Tomography (Springer-Verlag, 2005).