Coronary microvascular dysfunction: An update

European Heart Journal

Volumn 35, Issue 17, 2014, Pages 1101-1111

  Crea, Filippo ^a   Camici, Paolo G ^b   Merz, Cathleen Noel Bairey ^c  

^a CATHOLIC UNIVERSITY   (Italy)

^b SAN RAFFAELE HOSPITAL   (Italy)

^c CEDARS SINAI MEDICAL CENTER   (United States)

Author keywords

Acute coronary syndromes; Coronary microvascular dysfunction; Coronary microvascular obstruction; Myocardial diseases; Stable angina

Indexed keywords

BETA ADRENERGIC RECEPTOR BLOCKING AGENT; CALCIUM ANTAGONIST; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; DISOPYRAMIDE; DOXAZOSIN; FASUDIL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; IMIPRAMINE; IVABRADINE; NICORANDIL; NITRIC ACID DERIVATIVE; PLACEBO; RANOLAZINE; VERAPAMIL; XANTHINE DERIVATIVE;

ACUTE CORONARY SYNDROME; AORTA STENOSIS; ATHEROSCLEROSIS; CARDIOPULMONARY BYPASS; CHRONIC INFLAMMATION; CONGESTIVE CARDIOMYOPATHY; CORONARY ARTERY DISEASE; CORONARY MICROVASCULAR DYSFUNCTION; DIABETES MELLITUS; HUMAN; HYPERTROPHIC CARDIOMYOPATHY; IATROGENIC DISEASE; INFILTRATIVE CARDIAC DISEASE; MICROANGIOPATHY; MYOCARDIAL DISEASE; MYOCARDITIS; NONHUMAN; PERCUTANEOUS CORONARY INTERVENTION; PRIORITY JOURNAL; REVIEW; RISK FACTOR; SYNDROME X; TAKOTSUBO CARDIOMYOPATHY; AORTIC VALVE STENOSIS; CARDIOMYOPATHIES; CLASSIFICATION; COMPLICATION; CORONARY STENOSIS; FORECASTING; MICROVASCULAR ANGINA;

ACUTE CORONARY SYNDROME; AORTIC VALVE STENOSIS; CARDIOMYOPATHIES; CORONARY ARTERY DISEASE; CORONARY STENOSIS; FORECASTING; HUMANS; MICROVASCULAR ANGINA; PERCUTANEOUS CORONARY INTERVENTION; RISK FACTORS;

EID: 84899686463     PISSN: 0195668X     EISSN: 15229645     Source Type: Journal    
DOI: 10.1093/eurheartj/eht513     Document Type: Review

References (161)

1. Patel MR, Peterson ED, Dai D, Brennan JM, Redberg RF, Anderson HV, Brindis RG, Douglas PS. Low diagnostic yield of elective coronary angiography. N Engl J Med 2010;362:886-895
2. Cannon RO, Epstein SE. 'Microvascular angina' as a cause of chest pain with angiographically normal coronary arteries. Am J Cardiol 1988;61:1338-1343
3. Epstein SE, Cannon RO. Site of increased resistance to coronary flow in patients with angina pectoris and normal epicardial coronary arteries. J Am Coll Cardiol 1986;8:459-461
4. Chareonthaitawee P, Kaufmann P, Rimoldi O, Camici PG. Heterogeneity of resting and hyperemic myocardial blood flow in healthy humans. Cardiovasc Res 2001;50: 151-161
5. Camici PG, Rimoldi OE. The clinical value of myocardial blood flow measurement. J Nucl Med 2009;50:1076-1087
6. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med 2007;356: 830-840
7. Förstermann U, Sessa WC. Nitric oxide synthases: Regulation and function. Eur Heart J 2012;33:829-837
8. Satoh K, Fukumoto Y, Shimokawa H. Rho-kinase: Important new therapeutic target in cardiovascular diseases. Am J Physiol Heart Circ Physiol 2011;301: H287-H296
9. Moreau P, d'Uscio LV, Luscher TF. Structure and reactivity of small arteries in aging. Cardiovasc Res 1998;37:247-253
10. Antony I, Nitenberg A, Foult JM, Aptecar E. Coronary vasodilator reserve in untreated and treated hypertensive patients with and without left ventricular hypertrophy. J Am Coll Cardiol 1993;22:514-520
11. Rizzoni D, Palombo C, Porteri E, Muiesan ML, Kozakova M, La Canna G, Nardi M, Guelfi D, Salvetti M, Morizzo C, Vittone F, Rosei EA. Relationships between coronary flow vasodilator capacity and small artery remodelling in hypertensive patients. J Hypertens 2003;21:625-631
12. Nahser PJ Jr, Brown RE, Oskarsson H, Winniford MD, Rossen JD. Maximal coronary flowreserve and metabolic coronary vasodilation in patients with diabetes mellitus. Circulation 1995;91:635-640
13. Nitenberg A, Valensi P, Sachs R, Dali M, Aptecar E, Attali JR. Impairment of coronary vascular reserve and ach-induced coronary vasodilation in Diabetic patients with angiographically normal coronary arteries and normal left ventricular systolic function. Diabetes 1993;42:1017-1025
14. Dayanikli F, Grambow D, Muzik O, Mosca L, Rubenfire M, Schwaiger M. Early detection of abnormal coronary flow reserve in asymptomatic men at high risk for coronary artery disease using positron emission tomography. Circulation 1994;90: 808-817
15. Kaufmann PA, Gnecchi-Ruscone T, Schafers KP, Luscher TF, Camici PG. Low density lipoprotein cholesterol and coronary microvascular dysfunction in hypercholesterolemia. J Am Coll Cardiol 2000;36:103-109
16. Dagres N, Saller B, Haude M, Husing J, von Birgelen C, Schmermund A, Sack S, Baumgart D, Mann K, Erbel R. Insulin sensitivity and coronary vasoreactivity: Insulin sensitivity relates to adenosine-stimulated coronary flow response in human subjects. Clin Endocrinol (Oxf) 2004;61:724-731
17. Tune JD, Gorman MW, Feigl EO. Matching coronary blood flow to myocardial oxygen consumption. J Appl Physiol 2004;97:404-415
18. Di Carli MF, Janisse J, Grunberger G, Ager J. Role of chronic hyperglycemia in the pathogenesis of coronary microvascular dysfunction in Diabetes. J Am Coll Cardiol 2003;41:1387-1393
19. ReavenGM. Role of insulin resistance in human Disease (syndrome X): An expanded definition. Annu Rev Med 1993;44:121-131
20. Jadhav S, FerrellW, Greer IA, Petrie JR, Cobbe SM, Sattar N. Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries: A randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 2006;48:956-963
21. Cavallo Perin P, Pacini G, Giunti S, Comune M, Conte MR, Cassader M, Pagano G. Microvascular angina (cardiological syndrome X) per se is not associated with hyperinsulinaemia or insulin resistance. Eur J Clin Invest 2000;30:481-486
22. Cosin-Sales J, Pizzi C, Brown S, Kaski JC. C-reactive protein, clinical presentation, and ischaemic activity in patients with chest pain and normal coronary angiograms. J Am Coll Cardiol 2003;41:1468-1474
23. Ishimori ML, Martin R, Berman DS, Goykhman P, Shaw LJ, Shufelt C, Slomka PJ, Thomson LE, Schapira J, Yang Y,Wallace DJ,Weisman MH, Bairey Merz CN. Myocardial ischemia in the absence of obstructive coronary artery disease in systemic lupus erythematosus. JACC Cardiovasc Imaging 2011;4:27-33
24. Recio-Mayoral A, Rimoldi OE, Camici PG, Kaski JC. Inflammation and microvascular dysfunction in cardiac syndromeXpatients without conventional risk factors for coronary artery disease. JACC Cardiovasc Imaging 2013;6:660-667
25. Tondi P, Santoliquido A, Di Giorgio A, Sestito A, Sgueglia GA, Flore R, Careri G, Pinnacchio G, Lanza GA, Crea F. Endothelial dysfunction as assessed by flowmediated dilation in patients with cardiac syndrome X: Role of inflammation. Eur Rev Med Pharmacol Sci 2011;15:1074-1077
26. Wessel TR, Arant CB, McGorray SP, Sharaf BL, Reis SE, Kerensky RA, von Mering GO, Smith KM, Pauly DF, Handberg EM, Mankad S, Olson MB, Johnson BD, Merz CN, Sopko G, Pepine CJ. Coronary microvascular reactivity is only partially predicted by atherosclerosis risk factors or coronary artery disease in women evaluated for suspected ischemia: Results from the NHLBI women's ischemia syndrome evaluation (WISE). Clin Cardiol 2007;30:69-74
27. Cox ID, Botker HE, Bagger JP, Sonne HS, Kristensen BO, Kaski JC. Elevated endothelin concentrations are associated with reduced coronary vasomotor responses in patients with chest pain and normal coronary arteriograms. J Am Coll Cardiol 1999;34:455-460
28. Ong P, Athanasiadis A, Borgulya G, Mahrholdt H, Kaski JC, Sechtem U. High prevalence of a pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary arteries. The ACOVA Study (AbnormalCOronaryVAsomotion in patients with stable angina and unobstructed coronary arteries). J Am Coll Cardiol 2023;59:655-662
29. Johnson BD, Shaw LJ, Pepine CJ, Reis SE, Kelsey SF, Sopko G, Rogers WJ, Mankad S, Sharaf BL, Bittner V, Bairey Merz CN. Persistent chest pain predicts cardiovascular events in women without obstructive coronary artery disease: Results from the NIH-NHLBI-sponsored women's ischemia syndrome evaluation (WISE) study. Eur Heart J 2006;27:1408-1415
30. Merz NB, Johnson BD, Kelsey PSF, Reis SE, Lewis JF, Reichek N, Rogers WJ, Pepine CF, Shaw LJ. Diagnostic, prognostic, and cost assessment of coronary artery disease in women. Am J Manag Care 2001;7:959-965
31. Shaw LJ, Bairey Merz CN, Pepine CJ, Reis SE, Bittner V, Kelsey SF, Olson M, Johnson BD, Mankad S, Sharaf BL, Rogers WJ,Wessel TR, Arant CB, Pohost GM, Lerman A, Quyyumi AA, Sopko G. Insights from the NHLBI-sponsored women's ischemia syndrome evaluation (WISE) study: Part i: Gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies. J Am Coll Cardiol 2006;47:S4-S20
32. Cannon RO, Camici PG, Epstein SE. Pathophysiological dilemma of syndrome X Circulation 1992;85:883-892
33. Panting JR, Gatehouse PD, Yang GZ, Grothues F, Firmin DN, Collins P, Pennell DJ. Abnormal subendocardial perfusion in cardiac syndromeXdetected by cardiovascular magnetic resonance imaging. N Engl J Med 2002;346:1948-1953
34. Buchthal SD, den Hollander JA, Bairey MerzCN, RogersWA, Pepine CJ, Reichek N, Reis S, Kelsey SF, Pohost GM. Metabolic evidence of myocardial ischemia by 31-P spectroscopy in women with chest pain but no significant coronary stenoses: Pilot phase results from the NHLBI-sponsored WISE study. N Engl J Med 2000;342: 829-835
35. Buffon A, Rigattieri S, Santini SA, Ramazzotti V, Crea F, Giardina B, Maseri A. Myocardial ischemia-reperfusion Damage after pacing-induced tachycardia in patients with cardiac syndrome X Am J Physiol Heart Circ Physiol 2000;279:H2627-H2633
36. Bairey Merz CN, Shaw LJ, Reis SE, Bittner V, Kelsey SF, Olson M, Johnson BD, Pepine CJ, Mankad S, Sharaf BL, Rogers WJ, Pohost GM, Lerman A, Quyyumi AA, Sopko G. Insights from the NHLBI-sponsored women's ischemia syndrome evaluation (WISE) study: Part ii: Gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease. J Am Coll Cardiol 2006;47:S21-S29
37. Maseri A, Crea F, Kaski JC, Crake T. Mechanisms of angina pectoris in syndrome X J Am Coll Cardiol 1991;17:499-506
38. Lamendola P, Lanza GA, Spinelli A, Sgueglia GA, Di Monaco A, Barone L, Sestito A, Crea F. Long-Term prognosis of patients with cardiac syndrome X Int J Cardiol 2010; 140:197-199
39. Gulati M, Cooper-DeHoff RM, McClure C, Johnson BD, Shaw LJ, Handberg EM, Zineh I, Kelsey SF, Arnsdorf MF, Black HR, Pepine CJ, Merz CN. Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: A report from the women's ischemia syndrome evaluation study and the St James women take heart project. Arch Intern Med 2009;169:843-850
40. Pepine CJ, Anderson RD, Sharaf BL, Reis SE, Smith KM, Handberg EM, Johnson BD, Sopko G, Bairey Merz CN. 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 2010;55:2825-2832
41. Jespersen L, Hvelplund A, Abildstrom SZ, Pedersen F, Galatius S, Madsen JK, Jorgensen E, Kelbaek H, Prescott E. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J 2012;33:734-744
42. Kaski JC. Overview of gender aspects of cardiac syndrome X Cardiovasc Res 2002; 53:620-626
43. Shaw LJ, Bugiardini R, Bairey Merz CN.Women and ischemic heart disease: Evolving knowledge. J Am Coll Cardiol 2009;54:1561-1575
44. Gulati M, Shaw LJ, Bairey Merz CN. Myocardial ischemia in women: Lessons from the NHLBI WISE study. Clin Cardiol 2012;35141-148
45. Lanza GA. Cardiac syndrome X: A critical overview and future perspectives. Heart 2007;93:159-166
46. Lanza GA, Manzoli A, Bia E, Crea F, Maseri A. Acute effects of nitrates on exercise testing in patients with syndrome X Clinical and pathophysiological implications. Circulation 1994;90:2695-2700
47. Bugiardini R, Manfrini O, Pizzi C, Fontana F, Morgagni G. Endothelial function predicts future development of coronary artery disease: A study of women with chest pain and normal coronary angiograms. Circulation 2004;109:2518-2523
48. Marroquin OC, Holubkov R, Edmundowicz D, Rickens C, Pohost G, Buchthal S, Pepine CJ, Sopko G, Sembrat RC, Meltzer CC, Reis SE. Heterogeneity of microvascular dysfunction in women with chest pain not attributable to coronary artery disease: Implications for clinical practice. Am Heart J 2003;145:628-635
49. Lanza GA, Buffon A, Sestito A, Natale L, Sgueglia GA, Galiuto L, Infusino F, Mariani L, Centola A, Crea F. Relation between stress-induced myocardial perfusion Defects on cardiovascular magnetic resonance and coronary microvascular dysfunction in patients with cardiac syndrome X J Am Coll Cardiol 2008;51:466-472
50. Sestito A, Lanza GA, Di Monaco A, Lamendola P, Careri G, Tarzia P, Pinnacchio G, Battipaglia I, Crea F. Relation between cardiovascular risk factors and coronary microvascular dysfunction in cardiac syndrome X J Cardiovasc Med 2011;12: 322-327
51. Lanza GA, Crea F. Primary coronary microvascular dysfunction: Clinical presentation, pathophysiology, and management. Circulation 2010;121:2317-2325
52. Cavusoglu Y, Entok E, Timuralp B, Vardareli E, Kudaiberdieva G, Birdane A, Gorenek B, Unalir A, Goktekin O, Ata N. Regional distribution and extent of perfusion abnormalities, and the lung to heart uptake ratios during exercise thallium-201 SPECT imaging in patients with cardiac syndrome X Can J Cardiol 2005;21:57-62
53. Pizzi C, Manfrini O, Fontana F, Bugiardini R. Angiotensin-converting enzyme inhibitors and 3-hydroxy-3-methylglutaryl coenzyme a reductase in cardiacsyndrome X: Role of superoxide dismutase activity. Circulation 2004;109:53-58
54. Wei J, Mehta PK, Johnson BD, Samuels B, Kar S, Anderson RD, Azarbal B, Petersen J, Sharaf B, Handberg E, Shufelt C, Kothawade K, Sopko G, Lerman A, Shaw L, Kelsey SF, Pepine CJ, Merz CN. Safety of coronary reactivity testing in women with no obstructive coronary artery disease: Results from the NHLBI-sponsored WISE (women's ischemia syndrome evaluation) study. JACC Cardiovasc Interv 2012;5:646-653
55. von Mering GO, Arant CB,Wessel TR, McGorray SP, Bairey Merz CN, Sharaf BL, Smith KM, Olson MB, Johnson BD, Sopko G, Handberg E, Pepine CJ, Kerensky RA. Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: Results from the national heart, lung, and blood institute-sponsored women's ischemia syndrome evaluation (WISE). Circulation 2004;109:722-725
56. JCS JointWorking Group. Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (JCS 2008). Circ J 2010;74:1745-1762
57. Bugiardini R, Bairey Merz CN. Angina with 'normal' coronary arteries: A changing philosophy. JAMA 2005;293:477-484
58. Humphries KH, Pu A, Gao M, Carere RG, Pilote L. Angina with 'normal' coronary arteries: Sex differences in outcomes. Am Heart J 2008;155:375-381
59. Blomkalns AL, Chen AY, Hochman JS, Peterson ED, Trynosky K, Diercks DB, Brogan GX Jr, Boden WE, Roe MT, Ohman EM, Gibler WB, Newby LK. Gender disparities in the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: Large-scale observations from the crusade (can rapid risk stratification of unstable angina patients suppress adverse outcomes with early implementation of the American College of Cardiology/American Heart Association Guidelines) national quality improvement initiative. J Am Coll Cardiol 2005; 45:832-837
60. Vaccarino V, Badimon L, Corti R, de Wit C, Dorobantu M, Hall A, Koller A, Marzilli M, Pries A, Bugiardini R. Ischaemic heart disease in women: Are there sex differences in pathophysiology and risk factors?. Position paper from the working group on coronary pathophysiology and microcirculation of the European Society of Cardiology. Cardiovasc Res 2011;90:9-17
61. Elesber A, Lerman A, Bybee KA, Murphy JG, Barsness G, Singh M, Rihal CS, Prasad A. Myocardial perfusion in apical ballooning syndrome correlate of myocardial injury. Am Heart J 2006;152:469 e9-469e13
62. Rigo F, Sicari R, Citro R, Ossena G, Buja P, Picano E. Diffuse, marked, reversible impairment in coronary microcirculation in stress cardiomyopathy: A Doppler transthoracic echo study. Ann Med 2009;41:462-470
63. Feola M, Rosso GL, Casasso F, Morena L, Biggi A, Chauvie S, Ribichini F, Uslenghi E. Reversible inverse mismatch in transient left ventricular apical ballooning: Perfusion/ metabolism positron emission tomography imaging. J Nucl Cardiol 2006;13: 587-590
64. Galiuto L, De Caterina AR, Porfidia A, Paraggio L, Barchetta S, Locorotondo G, Rebuzzi AG, Crea F. Reversible coronary microvascular dysfunction: A common pathogenetic mechanism in apical ballooning or Takotsubo syndrome. Eur Heart J 2010;31:1319-1327
65. Barletta G, Del Pace S, Boddi M, Del Bene R, Salvadori C, Bellandi B, Coppo M, Saletti E, Gensini GF. Abnormal coronary reserve and left ventricular wall motion During cold pressor test in patients with previous left ventricular ballooning syndrome. Eur Heart J 2009;30:3007-3014
66. Martin EA, Prasad A, Rihal CS, Lerman LO, Lerman A. Endothelial function and vascular response to mental stress are impaired in patients with apical ballooning syndrome. J Am Coll Cardiol 2010;56:1840-1846
67. Cecchi F, Olivotto I, Gistri R, Lorenzoni R, Chiriatti G, Camici PG. Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. N Engl J Med 2003;349:1027-1035
68. Olivotto I, Girolami F, Sciagra' R, Ackerman MJ, Sotgia B, Bos JM, Nistri S, Sgalambro A, Grifoni C, Torricelli F, Camici PG, Cecchi F. Microvascular function is selectively impaired in patients with hypertrophic cardiomyopathy and sarcomere myofilament gene mutations. J Am Coll Cardiol 2011;58:839-848
69. Kwon DH, Smedira NG, Rodriguez ER, Tan C, Setser R, Thamilarasan M, LytleBW, LeverHM, DesaiMY. Cardiac magnetic resonance detection of myocardial scarring in hypertrophic cardiomyopathy: Correlation with histopathology and prevalence of ventricular tachycardia. J Am Coll Cardiol 2009;54:242-249
70. Petersen SE, Jerosch-Herold M, Hudsmith LE, Robson MD, Francis JM, Doll HA, Selvanayagam JB, Neubauer S,Watkins H. Evidence for microvascular dysfunction in hypertrophic cardiomyopathy: New insights from multiparametric magnetic resonance imaging. Circulation 2007;115:2418-2425
71. Maron MS, Olivotto I, Maron BJ, Prasad SK, Cecchi F, Udelson JE, Camici PG. The case for myocardial ischemia in hypertrophic cardiomyopathy. J Am Coll Cardiol 2009;54:866-875
72. Maron BJ. Hypertrophic cardiomyopathy: A systematic review. JAMA 2002;287: 1308-1320
73. Green JJ, Berger JS, Kramer CM, Salerno M. Prognostic value of late gadolinium enhancement in clinical outcomes for hypertrophic cardiomyopathy. JACC Cardiovasc Imaging 2012;5:370-377
74. Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ, Seidman CE, Shah PM, Spencer WH III, Spirito P, Ten Cate FJ, Wigle ED; ACC/ESC clinical expert consensus document on hypertrophic cardiomyopathy: A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines (Committee to Develop an Expert Consensus Document on Hypertrophic Cardiomyopathy). Eur Heart J 2003;24:1965-1991
75. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ, Seidman C, Young JB. Contemporary definitions and classification of the cardiomyopathies. An American Heart Association scientific statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology InterdisciplinaryWorking Groups; and Council on Epidemiology and Prevention. Circulation 2006;113:1807-1816
76. Neglia D, Parodi O, Gallopin M, Sambuceti G, Giorgetti A, Pratali L, Salvadori P, Michelassi C, Lunardi M, Pelosi G, Marzilli M, L'Abbate A. Myocardial blood flow response to pacing tachycardia and to dipyridamole infusion in patients with dilated cardiomyopathy without overt heart failure. A quantitative assessment by positron emission tomography. Circulation 1995;92:796-804
77. Noue T, Sakai Y, Morooka S, Hayashi T, Takaianagi K, Yamanaka T, Kakoi H, Takabatake Y. Coronary flow reserve in patients with dilated cardiomyopathy. Am Heart J 1993;125:93-98
78. Koutalas E, Kanoupakis E, Vardas P. Sudden cardiac death in non-ischaemic dilated cardiomyopathy: A critical appraisal of existing and potential risk stratification tools. Int J Cardiol 2013;167:335-341
79. Lehrke S, Lossnitzer D, Schöb M, Steen H, Merten C, Kemmling H, Pribe R, Ehlermann P, Zugck C, Korosoglou G, Giannitsis E, KatusHA. Use of cardiovascular magnetic resonance for risk stratification in chronic heart failure: Prognostic value of late gadolinium enhancement in patients with non-ischaemic dilated cardiomyopathy. Heart 2011;97:727-732
80. Kandolf R. Virus etiology of inflammatory cardiomyopathy. Dtsch MedWochenschr 2004;129:2187-2192
81. Mahrholdt H, Wagner A, Deluigi CC, Kispert E, Hager S, Meinhardt G, Vogelsberg H, Fritz P, Dippon J, Bock CT, Klingel K, Kandolf R, Sechtem U. Presentation, patterns of myocardial damage, and clinical course of viral myocarditis. Circulation 2006;114:1581-1590
82. Brown KE, Anderson SM, Young NS. Erythrocyte P antigen: Cellular receptor for B19 parvovirus. Science 1993;262:114-117
83. Kuhl U, Pauschinger M, Bock T, Klingel K, Schwimmbeck CP, Seeberg B, Krautwurm L, PollerW, Schultheiss HP, Kandolf R. Parvovirus B19 infection mimicking acute myocardial infarction. Circulation 2003;108:945-950
84. Yilmaz A, Mahrholdt H, Athanasiadis A, Vogelsberg H, Meinhardt G, Voehringer M, Kispert EM, Deluigi C, Baccouche H, Spodarev E, Klingel K, Kandolf R, Sechtem U. Coronary vasospasm as the underlying cause for chest pain in patients with PVB19 myocarditis. Heart 2008;94:1456-1463
85. Gould KL, Carabello BA.Whyangina in aortic stenosis with normal coronary arteriograms?. Circulation 2003;107:3121-3123
86. Ross J Jr, Braunwald E. Aortic stenosis. Circulation 1968;38:61-67
87. Marcus ML, Doty DB, Hiratzka LF, Marcus ML. Decreased coronary reserve: A mechanism for angina pectoris in patients with aortic stenosis and normal coronary arteries. N Engl J Med 1982;307:1362-1366
88. Dunn RB, Griggs DM. Ventricular filling pressure as a determinant of coronary blood flow during ischemia. Am J Physiol Heart Circ Physiol 1983;244:H429-H436
89. Breisch EA, Houser SR, Carey RA, Spann JF, Bove AA. Myocardial blood flow and capillary density in chronic pressure overload of the feline left ventricle. Cardiovasc Res 1980;14:469-475
90. Schwartzkopff B, Frenzel H, Dieckerhoff J, Betz P, Flasshove M, Schulte HD, Mundhenke M, Motz W, Strauer BE. Morphometric investigation of human myocardium in arterial hypertension and valvular aortic stenosis. Eur Heart J 1992; 13(Suppl D):17-23
91. Rajappan K, Rimoldi OE, Dutka DP, Ariff B, Pennell DJ, Sheridan DJ, Camici PG. Mechanisms of coronary microcirculatory dysfunction in patients with aortic stenosis and angiographically normal coronary arteries. Circulation 2002;105:470-476
92. Niccoli GP, Giubilato S, Di Vito L, Leo A, Cosentino N, Pitocco D, Marco V, Ghirlanda G, Prati F, Crea F. Severity of coronary atherosclerosis in patients with a first acute coronary event: A diabetes paradoX Eur Heart J 2013;34:729-741
93. Stergiopoulos K, Brown DL. Initial coronary stent implantation with medical therapy vs medical therapy alone for stable coronary artery disease: Meta-Analysis of randomized controlled trials. Arch Intern Med 2012;172:312-319
94. Lerman A, Holmes DR, Herrmann J, Gersh BJ. Microcirculatory dysfunction in ST-elevation myocardial infarction: Cause, consequence, or both?. Eur Heart J 2007;28:788-797
95. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative reviewof 23 randomised trials. Lancet 2003;361:13-20
96. Rezkalla SH, Kloner RA. Coronary no-reflowphenomenon: From the experimental laboratory to the cardiac catheterization laboratory. Catheter Cardiovasc Interv 2008;72:950-957
97. LincoffAM, Topol EJ. Illusion of reperfusion. Does anyone achieve optimal reperfusion During acute myocardial infarction?. Circulation 1993;88:1361-1374
98. Niccoli G, Burzotta F, Galiuto L, Crea F. Myocardial no-reflow in humans. J Am Coll Cardiol 2009;54:281-292
99. Niccoli G, Kharbanda RK, Crea F, BanningAP. No-reflow:again prevention is better than treatment. Eur Heart J 2010;31:2449-2555
100. Brosh D, Assali AR, Mager A et al. Effect of no-reflowduring primary percutaneous coronary intervention for acute myocardial infarction on six-month mortality.Am J Cardiol 2007;99:442-445
101. Bolognese L, Carrabba N, Parodi G, Santoro GM, Buonamici P, Cerisano G, Antoniucci D. Impact of microvascular dysfunction on left ventricular remodeling and long-Term clinical outcome after primary coronary angioplasty for acute myocardial infarction. Circulation 2004;109:1121-1126
102. Montalescot G, Ongen Z, Guindy R, Sousa A, Lu SZ, Pahlajani D, Pellois A, Vicaut E; for the RIVIERA Investigators. Predictors of outcome in patients undergoing PCI. Results of the RIVIERA study. Int J Cardiol 2008;129:379-387
103. Collet JP, Montalescot G. The acute reperfusion management of STEMI in patients with impaired glucose tolerance and type 2 diabetes. Diabetes Vasc Dis Res 2005;2: 136-143
104. GolinoP, MarokoPR, CarewTE. The effect of acute hypercholesterolemia on myocardial infarct size and the no-reflow phenomenon During coronary occlusionreperfusion. Circulation 1987;75:292-298
105. Rezkalla SH, Kloner RA. Ischaemic preconditioning and preinfarction angina in the clinical arena. Nat Clin Pract Cardiovasc Med 2004;1:96-102
106. Testa L, Van Gaal WJ, Biondi Zoccai GG, Agostoni P, Latini RA, Bedogni F, Porto I, Banning AP. Myocardial infarction after percutaneous coronary intervention: A meta-Analysis of troponin elevation applying the new universal definition. QJM 2009;102:369-378
107. Uren NG, Crake T, Lefroy DC, de Silva R, Davies GJ, Maseri A. Delayed recovery of coronary resistive vessel function after coronary angioplasty. J Am Coll Cardiol 1993; 21:612-662
108. Gulielmos V, Menschikowski M, Dill H, Eller M, Thiele S, Tugtekin SM, JarossW, Schueler S. Interleukin-1, interleukin-6 and myocardial enzyme response after coronary artery bypass grafting-A prospective randomized comparison of the conventional and three minimally invasive surgical techniques. Eur J Cardiothorac Surg 2000;18:594-601
109. Clive Landis R, Murkin JM, Stump DA, Baker RA, Arrowsmith JE, De Somer F, Dain SL, Dobkowski WB, Ellis JE, Falter F, Fischer G, Hammon JW, Jonas RA, Kramer RS, Likosky DS, Paget Milsom F, Poullis M, Verrier ED, Walley K, Westaby S. Consensus statement: Minimal criteria for reporting the systemic inflammatory response to cardiopulmonary bypass. Heart Surg Forum 2010;13: E116-E123
110. Ren G, Dewald O, Frangogiannis NG. Inflammatory mechanisms in myocardial infarction. Curr Drug Targets Inflamm Allergy 2003;2:242-256
111. Frangogiannis NG, SmithCW, Entman ML. The inflammatory response in myocardial infarction. Cardiovasc Res 2002;53:31-47
112. Spyrou N, Khan MA, Rosen SD, Jagathesan R, Foale R, DaviesW, Sogliani F, De Lisle Stanbridge R, Camici PG. Persistent but reversible coronary microvascular dysfunction after bypass grafting. Am J Physiol 2000;279:H2634-H2640
113. Lim CC, Cuculi F, van Gaal WJ, Testa L, Arnold JR, Karamitsos T, Francis JM, Digby JE, Antoniades C, Kharbanda RK, Neubauer S, Westaby S, Banning AP. Early diagnosis of perioperative myocardial infarction after coronary bypass grafting: A study using biomarkers and cardiac magnetic resonance imaging. Ann Thorac Surg 2011;92:2046-2053
114. Croal BL, Hillis GS, Gibson PH, Fazal MT, El-Shafei H, Gibson G, Jeffrey RR, Buchan KG, West D, Cuthbertson BH. Relationship between postoperative cardiac troponin I levels and outcome of cardiac surgery. Circulation 2006;114: 1468-1475
115. Neglia D, Fommei E, Varela-Carver A, Mancini M, Ghione S, Lombardi M, Pisani P, Parker H, d'Amati G, Donato L, Camici PG. Treatment of hypertension with perindopril plus indapamide leads to reverse coronary microvascular remodelling and improved blood flow. J Hypertens 2011;29:364-372
116. Lim TK, Choy AJ, Khan F, Belch JJ, Struthers AD, Lang CC. Therapeutic development in cardiac syndrome X: A need to target the underlying pathophysiology. Cardiovasc Ther 2009;27:49-58
117. ErikssonBE, Tyni-Lenne R, Svedenhag J, Hallin R, Jensen-Urstad K, Jensen-Urstad M, Bergman K, Selven C. Physical training in syndrome X: Physical training counteracts deconditioning and pain in syndrome X J Am Coll Cardiol 2000;36:1619-1625
118. Kayikcioglu M, Payzin S, Yavuzgil O, Kultursay H, Can LH, Soydan I. Benefits of statin treatment in cardiac syndrome-X Eur Heart J 2003;24:1999-2005
119. Chen JW, HsuNW, Wu TC, Lin SJ, Chang MS. Long-Term angiotensin-converting enzyme inhibition reduces plasma asymmetric dimethylarginine and improves endothelial nitric oxide bioavailability and coronary microvascular function in patients with syndrome X Am J Cardiol 2002;90:974-982
120. Sutsch G, Oechslin E, Mayer I, Hess OM. Effect of diltiazem on coronary flow reserve in patients with microvascular angina. Int J Cardiol 1995;52:135-143
121. Lanza GA, Colonna G, Pasceri V, Maseri A. Atenolol versus amlodipine versus isosorbide-5-mononitrate on anginal symptoms in syndrome X Am J Cardiol 1999;84:854-856
122. Kaski JC, RosanoGMC, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA. Cardiac syndrome X: Clinical characteristics and left ventricular function: Long-Term follow-up study. J Am Coll Cardiol 1995;25:807-814
123. Mehta PK, Goykhman P, Thomson LE, Shufelt C,Wei J, Yang Y, Gill E, Minissian M, Shaw LJ, Slomka PJ, Slivka M, Berman DS, Bairey Merz CN. Ranolazine improves angina inwomenwith evidence of myocardial ischemia but noobstructive coronary artery disease. JACC Cardiovasc Imaging 2011;4:514-522
124. Villano A, Di Franco A, Nerla R, Sestito A, Tarzia P, Lamendola P, Di Monaco A, Sarullo FM, Lanza GA, Crea F. Effects of ivabradine and ranolazine in patients with microvascular angina pectoris. Am J Cardiol 2013;112:8-13
125. Emdin M, Picano E, Lattanzi F, L'Abbate A. Improved exercise capacity with acute aminophylline administration in patients with syndrome X J Am Coll Cardiol 1989; 14:1450-1453
126. Elliott PM, Krzyzowska-Dickinson K, Calvino R, Hann C, Kaski JC. Effect of oral aminophylline in patients with angina and normal coronary arteriograms (syndrome X). Heart 1997;77:523-526
127. Crea F, Gaspardone A, Araujo L, Da Silva R, Kaski JC, Davies G, Maseri A. Effects of aminophylline on cardiac function and regional myocardial perfusion: Implications regarding its antiischaemic action. Am Heart J 1994;127:817-824
128. Crea F, Pupita G, Galassi AR, el-Tamimi H, Kaski JC, Davies G, Maseri A. Role of adenosine in pathogenesis of anginal pain. Circulation 1990;81:164-172
129. Chen JW, Lee WL, HsuNW, Lin SJ, Ting CT,Wang SP, Chang MS. Effects of shortterm treatment of nicorandil on exercise-induced myocardial ischemia and abnormal cardiacautonomic activity in microvascular angina.AmJ Cardiol 1997;80:32-38
130. Botker HE, Sonne HS, Schmitz O, Nielsen TT. Effects of doxazosin on exercise-induced angina pectoris, ST-segment depression, and insulin sensitivity in patients with syndrome X Am J Cardiol 1998;82:1352-1356
131. Mohri M, Shimokawa H, Hirakawa Y, Masumoto A, Takeshita A. Rho-kinase inhibition with intracoronary fasudil prevents myocardial ischemia in patients with coronary microvascular spasm. J Am Coll Cardiol 2003;41:15-19
132. Cannon RO III, Quyyumi AA, Mincemoyer R, Stine AM, Gracely RH, Smith WB, Geraci MF, Black BC, UhdeTW,Waclawiw MA, Maher K, Benjamin SB. Imipramine in patients with chest pain Despite normal coronary angiograms.NEngl J Med 1994; 330:1411-1417
133. Adamson DL,Webb CM, Collins P. Esterified estrogens combined with methyltestosterone improve emotional well-being in postmenopausal women with chest pain and normal coronary angiograms. Menopause 2001;8:233-238
134. Sgueglia GA, Sestito A, Spinelli A, Cioni B, Infusino F, Papacci F, Bellocci F, Meglio M, Crea F, Lanza GA. Long-Term follow-up of patients with cardiac syndrome X treated by spinal cord stimulation. Heart 2007;93:591-597
135. Kronhaus KD, Lawson WE. Enhanced external counterpulsation is an effective treatment for Syndrome X Int J Cardiol 2009;135:256-257
136. Jaber WA, Yang EH, Nishimura RA, Sorajja P, Rihal CS, Elesber A, Eeckhout E, Lerman A. Immediate improvement in coronary flow reserve after alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy. Heart 2009; 95:564-569
137. Soliman OI, Geleijnse ML, Michels M, Dijkmans PA, Nemes A, van Dalen BM, Vletter WB, Serruys PW, ten Cate FJ. Effect of successful alcohol septal ablation on microvascular function in patients with obstructive hypertrophic cardiomyopathy. Am J Cardiol 2008;101:1321-1327
138. Choudhury L, Elliott P, Rimoldi O, Ryan M, Lammertsma AA, Boyd H, McKenna WJ, Camici PG. Transmural myocardial blood flow distribution in hypertrophic cardiomyopathy and effect of treatment. Basic Res Cardiol 1999;94:49-59
139. Gistri R, Cecchi F, Choudhury L, Montereggi A, Sorace O, Salvadori PA, Camici PG. Effect of verapamil on absolute myocardial blood flow in hypertrophic cardiomyopathy. Am J Cardiol 1994;74:363-368
140. Hongo M, NakatsukaT, Takenaka H, Tanaka M,Watanabe N, YazakiY, Sekiguchi M. Effects of intravenous disopyramide on coronary hemodynamics and vasodilator reserve in hypertrophic obstructive cardiomyopathy. Cardiology 1996;87:6-11
141. Kyriakidis M, Triposkiadis F, Dernellis J, Androulakis AE, Mellas P, Kelepeshis GA, Gialafos JE. Effects of cardiac versus circulatory angiotensin-converting enzyme inhibition on left ventricular diastolic function and coronary blood flow in hypertrophic obstructive cardiomyopathy. Circulation 1998;97:1342-1347
142. Erdogan D, Gullu H, Caliskan M, Ciftci O, Baycan S, Yildirir A, Muderrisoglu H. Nebivolol improves coronary flow reserve in patients with idiopathic dilated cardiomyopathy. Heart 2007;93:319-324
143. FanY, Lin JH,DongG, ZhuJ, Yin F, Yang SS. The effect of carvedilol oncoronaryflow reserve in patients with dilated cardiomyopathy. Zhonghua Nei Ke Za Zhi 2010;49: 217-219
144. Neglia D, Sambuceti G, Giorgetti A, Bartoli M, Salvadori P, Sorace O, Puccini G, L'Abbate A, Parodi O. Effects of long-Term treatment with verapamil on left ventricular function and myocardial blood flow in patients with dilated cardiomyopathy without overt heart failure. J Cardiovasc Pharmacol 2000;36:744-750
145. Erdogan D, Tayyar S, Uysal BA, Icli A, Karabacak M, Ozaydin M, Dogan A. Effects of allopurinol on coronary microvascular and left ventricular function in patients with idiopathic dilated cardiomyopathy. Can J Cardiol 2012;28:721-727
146. Chilian WM, Penn MS, Pung YF, Dong F, Mayorga M, Ohanyan V, Logan S, Yin L. Coronary collateral growth-back to the future. J Mol Cell Cardiol 2012;52: 905-911
147. Henry TD, Grines CL,WatkinsMW, Dib N, Barbeau G, Moreadith R, Andrasfay T, Engler RL. Effects of Ad5FGF-4 in patients with angina: An analysis of pooled data from the AGENT-3 and AGENT-4 trials. J Am Coll Cardiol 2007;50:1038-1046
148. LosordoDW, Henry TD, Davidson C, Sup Lee J, CostaMA, Bass T, Mendelsohn F, Fortuin FD, Pepine CJ, Traverse JH, Amrani D, Ewenstein BM, Riedel N, Story K, Barker K, Povsic TJ, Harrington RA, Schatz RA; ACT34-CMI Investigators. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ Res 2011; 109:428-436
149. Burzotta F, Trani C, Romagnoli E, Mazzari MA, Rebuzzi AG, De Vita M, Garramone B, Giannico F, Niccoli G, Biondi-Zoccai GG, Schiavoni G, Mongiardo R, Crea F. Manual thrombus-Aspiration improves myocardial reperfusion: The randomized evaluation of the effect of mechanical reduction of distal embolization by thrombus-Aspiration in primary and rescue angioplasty (REMEDIA) trial. J Am Coll Cardiol 2005;46:371-376
150. Silva-Orrego P, Colombo P, Bigi R, Gregori D, Delgado A, Salvade P, Oreglia J, Orrico P, de Biase A, Piccalò G, Bossi I, Klugmann S. Thrombus aspiration before primary angioplasty improves myocardial reperfusion in acute myocardial infarction: The DEAR-MI (Dethrombosis to Enhance Acute Reperfusion in Myocardial Infarction) study. J Am Coll Cardiol 2006;48:1552-1559
151. Vlaar PJ, Svilaas T, van Der Horst IC, Diercks GF, Fokkema ML, de Smet BJ, van Den Heuvel AF, Anthonio RL, Jessurun GA, Tan ES, Suurmeijer AJ, Zijlstra F. Cardiac deathand reinfarction after1 year in the ThrombusAspiration During Percutaneous coronary intervention in Acute myocardial infarction Study (TAPAS): A 1-year follow-up study. Lancet 2008;371:1915-1920
152. Svilaas T, Vlaar PJ, van Der Horst IC, Diercks GF, de Smet BJ, van Den Heuvel AF, Anthonio RL, Jessurun GA, Tan ES, Suurmeijer AJ, Zijlstra F. Thrombus aspiration During primary percutaneous coronary intervention. N Engl J Med 2008;358: 557-567
153. Fröbert O, Lagerqvist B, Olivecrona GK, Omerovic E, Gudnason T, Maeng M, Aasa M, Angerås O, Calais F, Danielewicz M, Erlinge D, Hellsten L, Jensen U, Johansson AC, Kåregren A, Nilsson J, Robertson L, Sandhall L, Sjögren I, Ostlund O, Harnek J, James SK Thrombus aspiration During ST-segment elevation myocardial infarction. N Engl J Med 2013;369:1587-1597
154. Niccoli G, Rigattieri S,DeVita MR, Valgimigli M, CorvoP, Fabbiocchi F, Romagnoli E, De Caterina AR, La Torre G, Lo Schiavo P, Tarantino F, Ferrari R, Tomai F, Olivares P, Cosentino N, D'Amario D, Leone AM, Porto I, Burzotta F, Trani C, Crea F. Open-label, randomized, placebo controlled evaluation of intracoronary adenosine or nitroprusside after thrombus aspiration During primary percutaneous coronary intervention for the prevention of microvascular obstruction in acute myocardial infarction: The REOPEN-AMI study. JACC Cardiovasc Interv 2013;6: 580-589
155. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: A delay of lethal cell injury in ischaemic myocardium. Circulation 1986;74:1124-1136
156. Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I, Aupetit JF, Bonnefoy E, Finet G, André-Fouët X, Ovize M. Postconditioning the human heart. Circulation 2005;112:2143-2148
157. Thibault H, Piot C, Staat P, Bontemps L, Sportouch C, Rioufol G, Cung TT, Bonnefoy E, Angoulvant D, Aupetit JF, Finet G, André-Fouët X, Macia JC, Raczka F, Rossi R, Itti R, Kirkorian G, Derumeaux G, Ovize M. Long term benefit of postconditioning. Circulation 2008;117:1037-1044
158. Bøtker HE, Kharbanda R, Schmidt MR, Bøttcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sørensen HT, Redington AN, Nielsen TT. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: A randomised trial. Lancet 2010;375:727-734
159. Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, André-Fouët X, Revel D, Kirkorian G, Monassier JP, Derumeaux G, Ovize M. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008;359:473-481
160. Mewton N, Croisille P, Gahide G, Rioufol G, Bonnefoy E, Sanchez I, Cung TT, Sportouch C, Angoulvant D, Finet G, André-Fouët X, Derumeaux G, Piot C, Vernhet H, Revel D, Ovize M. Effect of cyclosporine on left ventricular remodeling after reperfused myocardial infarction. J Am Coll Cardiol 2010;55:1200-1205
161. Kitakaze M, Asakura M, Kim J, Shintani Y, Asanuma H, Hamasaki T, Seguchi O, Myoishi M, Minamino T, Ohara T, Nagai Y, Nanto S, Watanabe K, Fukuzawa S, Hirayama A, Nakamura N, Kimura K, Fujii K, Ishihara M, Saito Y, Tomoike H, Kitamura S; J-WIND investigators. Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): Two randomised trials. Lancet 2007;370:1483-1493