Effects of sex on coronary microvascular dysfunction and cardiac outcomes.
BACKGROUND
Coronary microvascular dysfunction (CMD) is a prevalent and prognostically important finding in patients with symptoms suggestive of coronary artery disease. The relative extent to which CMD affects both sexes is largely unknown.


RESULTS
We investigated 405 men and 813 women who were referred for evaluation of suspected coronary artery disease with no previous history of coronary artery disease and no visual evidence of coronary artery disease on rest/stress positron emission tomography myocardial perfusion imaging. Coronary flow reserve was quantified, and coronary flow reserve <2.0 was used to define the presence of CMD. Major adverse cardiac events, including cardiac death, nonfatal myocardial infarction, late revascularization, and hospitalization for heart failure, were assessed in a blinded fashion over a median follow-up of 1.3 years (interquartile range, 0.5-2.3 years). CMD was highly prevalent both in men and women (51% and 54%, respectively; Fisher exact test =0.39; equivalence P=0.0002). Regardless of sex, coronary flow reserve was a powerful incremental predictor of major adverse cardiac events (hazard ratio, 0.80 [95% confidence interval, 0.75-086] per 10% increase in coronary flow reserve; P<0.0001) and resulted in favorable net reclassification improvement (0.280 [95% confidence interval, 0.049-0.512]), after adjustment for clinical risk and ventricular function. In a subgroup (n=404; 307 women/97 men) without evidence of coronary artery calcification on gated computed tomography imaging, CMD was common in both sexes, despite normal stress perfusion imaging and no coronary artery calcification (44% of men versus 48% of women; Fisher exact test P=0.56; equivalence P=0.041).


CONCLUSIONS
CMD is highly prevalent among at-risk individuals and is associated with adverse outcomes regardless of sex. The high prevalence of CMD in both sexes suggests that it may be a useful target for future therapeutic interventions.
From the Division of Cardiovascular Medicine, Department of Internal Medicine, and Divisions of Nuclear Medicine and Cardiothoracic Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI (V.L.M.); Noninvasive Cardiovascular Imaging Program, Departments of Internal Medicine and Radiology (V.L.M., M.N., V.R.T., S.D., R.B., M.F.D.C.), and Division of Cardiovascular Medicine, Department of Medicine (V.L.M., V.R.T., J.H., S.D., R.B., M.F.D.C.), Brigham & Women's Hospital, Boston, MA; Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (C.R.F., M.G., J.H., S.D., M.F.D.C.), and Istituto di Bioimmagini e Fisiologia Molecolare (O.R.), Consiglio Nazionale delle Ricerche and Scientific Institute San Raffaele, Milan, Italy; Division of Cardiology, Vita Salute University and Scientific Institute San Raffaele, Milan, Italy (P.G.C.).
Venkatesh L
VL
Murthy
From the Division of Cardiovascular Medicine, Department of Internal Medicine, and Divisions of Nuclear Medicine and Cardiothoracic Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI (V.L.M.); Noninvasive Cardiovascular Imaging Program, Departments of Internal Medicine and Radiology (V.L.M., M.N., V.R.T., S.D., R.B., M.F.D.C.), and Division of Cardiovascular Medicine, Department of Medicine (V.L.M., V.R.T., J.H., S.D., R.B., M.F.D.C.), Brigham & Women's Hospital, Boston, MA; Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (C.R.F., M.G., J.H., S.D., M.F.D.C.), and Istituto di Bioimmagini e Fisiologia Molecolare (O.R.), Consiglio Nazionale delle Ricerche and Scientific Institute San Raffaele, Milan, Italy; Division of Cardiology, Vita Salute University and Scientific Institute San Raffaele, Milan, Italy (P.G.C.).
Masanao
M
Naya
From the Division of Cardiovascular Medicine, Department of Internal Medicine, and Divisions of Nuclear Medicine and Cardiothoracic Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI (V.L.M.); Noninvasive Cardiovascular Imaging Program, Departments of Internal Medicine and Radiology (V.L.M., M.N., V.R.T., S.D., R.B., M.F.D.C.), and Division of Cardiovascular Medicine, Department of Medicine (V.L.M., V.R.T., J.H., S.D., R.B., M.F.D.C.), Brigham & Women's Hospital, Boston, MA; Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (C.R.F., M.G., J.H., S.D., M.F.D.C.), and Istituto di Bioimmagini e Fisiologia Molecolare (O.R.), Consiglio Nazionale delle Ricerche and Scientific Institute San Raffaele, Milan, Italy; Division of Cardiology, Vita Salute University and Scientific Institute San Raffaele, Milan, Italy (P.G.C.).
Viviany R
VR
Taqueti
From the Division of Cardiovascular Medicine, Department of Internal Medicine, and Divisions of Nuclear Medicine and Cardiothoracic Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI (V.L.M.); Noninvasive Cardiovascular Imaging Program, Departments of Internal Medicine and Radiology (V.L.M., M.N., V.R.T., S.D., R.B., M.F.D.C.), and Division of Cardiovascular Medicine, Department of Medicine (V.L.M., V.R.T., J.H., S.D., R.B., M.F.D.C.), Brigham & Women's Hospital, Boston, MA; Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (C.R.F., M.G., J.H., S.D., M.F.D.C.), and Istituto di Bioimmagini e Fisiologia Molecolare (O.R.), Consiglio Nazionale delle Ricerche and Scientific Institute San Raffaele, Milan, Italy; Division of Cardiology, Vita Salute University and Scientific Institute San Raffaele, Milan, Italy (P.G.C.).
Courtney R
CR
Foster
From the Division of Cardiovascular Medicine, Department of Internal Medicine, and Divisions of Nuclear Medicine and Cardiothoracic Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI (V.L.M.); Noninvasive Cardiovascular Imaging Program, Departments of Internal Medicine and Radiology (V.L.M., M.N., V.R.T., S.D., R.B., M.F.D.C.), and Division of Cardiovascular Medicine, Department of Medicine (V.L.M., V.R.T., J.H., S.D., R.B., M.F.D.C.), Brigham & Women's Hospital, Boston, MA; Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (C.R.F., M.G., J.H., S.D., M.F.D.C.), and Istituto di Bioimmagini e Fisiologia Molecolare (O.R.), Consiglio Nazionale delle Ricerche and Scientific Institute San Raffaele, Milan, Italy; Division of Cardiology, Vita Salute University and Scientific Institute San Raffaele, Milan, Italy (P.G.C.).
Mariya
M
Gaber
From the Division of Cardiovascular Medicine, Department of Internal Medicine, and Divisions of Nuclear Medicine and Cardiothoracic Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI (V.L.M.); Noninvasive Cardiovascular Imaging Program, Departments of Internal Medicine and Radiology (V.L.M., M.N., V.R.T., S.D., R.B., M.F.D.C.), and Division of Cardiovascular Medicine, Department of Medicine (V.L.M., V.R.T., J.H., S.D., R.B., M.F.D.C.), Brigham & Women's Hospital, Boston, MA; Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (C.R.F., M.G., J.H., S.D., M.F.D.C.), and Istituto di Bioimmagini e Fisiologia Molecolare (O.R.), Consiglio Nazionale delle Ricerche and Scientific Institute San Raffaele, Milan, Italy; Division of Cardiology, Vita Salute University and Scientific Institute San Raffaele, Milan, Italy (P.G.C.).
Jon
J
Hainer
From the Division of Cardiovascular Medicine, Department of Internal Medicine, and Divisions of Nuclear Medicine and Cardiothoracic Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI (V.L.M.); Noninvasive Cardiovascular Imaging Program, Departments of Internal Medicine and Radiology (V.L.M., M.N., V.R.T., S.D., R.B., M.F.D.C.), and Division of Cardiovascular Medicine, Department of Medicine (V.L.M., V.R.T., J.H., S.D., R.B., M.F.D.C.), Brigham & Women's Hospital, Boston, MA; Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (C.R.F., M.G., J.H., S.D., M.F.D.C.), and Istituto di Bioimmagini e Fisiologia Molecolare (O.R.), Consiglio Nazionale delle Ricerche and Scientific Institute San Raffaele, Milan, Italy; Division of Cardiology, Vita Salute University and Scientific Institute San Raffaele, Milan, Italy (P.G.C.).
Sharmila
S
Dorbala
From the Division of Cardiovascular Medicine, Department of Internal Medicine, and Divisions of Nuclear Medicine and Cardiothoracic Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI (V.L.M.); Noninvasive Cardiovascular Imaging Program, Departments of Internal Medicine and Radiology (V.L.M., M.N., V.R.T., S.D., R.B., M.F.D.C.), and Division of Cardiovascular Medicine, Department of Medicine (V.L.M., V.R.T., J.H., S.D., R.B., M.F.D.C.), Brigham & Women's Hospital, Boston, MA; Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (C.R.F., M.G., J.H., S.D., M.F.D.C.), and Istituto di Bioimmagini e Fisiologia Molecolare (O.R.), Consiglio Nazionale delle Ricerche and Scientific Institute San Raffaele, Milan, Italy; Division of Cardiology, Vita Salute University and Scientific Institute San Raffaele, Milan, Italy (P.G.C.).
Ron
R
Blankstein
From the Division of Cardiovascular Medicine, Department of Internal Medicine, and Divisions of Nuclear Medicine and Cardiothoracic Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI (V.L.M.); Noninvasive Cardiovascular Imaging Program, Departments of Internal Medicine and Radiology (V.L.M., M.N., V.R.T., S.D., R.B., M.F.D.C.), and Division of Cardiovascular Medicine, Department of Medicine (V.L.M., V.R.T., J.H., S.D., R.B., M.F.D.C.), Brigham & Women's Hospital, Boston, MA; Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (C.R.F., M.G., J.H., S.D., M.F.D.C.), and Istituto di Bioimmagini e Fisiologia Molecolare (O.R.), Consiglio Nazionale delle Ricerche and Scientific Institute San Raffaele, Milan, Italy; Division of Cardiology, Vita Salute University and Scientific Institute San Raffaele, Milan, Italy (P.G.C.).
Ornella
O
Rimoldi
From the Division of Cardiovascular Medicine, Department of Internal Medicine, and Divisions of Nuclear Medicine and Cardiothoracic Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI (V.L.M.); Noninvasive Cardiovascular Imaging Program, Departments of Internal Medicine and Radiology (V.L.M., M.N., V.R.T., S.D., R.B., M.F.D.C.), and Division of Cardiovascular Medicine, Department of Medicine (V.L.M., V.R.T., J.H., S.D., R.B., M.F.D.C.), Brigham & Women's Hospital, Boston, MA; Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (C.R.F., M.G., J.H., S.D., M.F.D.C.), and Istituto di Bioimmagini e Fisiologia Molecolare (O.R.), Consiglio Nazionale delle Ricerche and Scientific Institute San Raffaele, Milan, Italy; Division of Cardiology, Vita Salute University and Scientific Institute San Raffaele, Milan, Italy (P.G.C.).
Paolo G
PG
Camici
From the Division of Cardiovascular Medicine, Department of Internal Medicine, and Divisions of Nuclear Medicine and Cardiothoracic Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI (V.L.M.); Noninvasive Cardiovascular Imaging Program, Departments of Internal Medicine and Radiology (V.L.M., M.N., V.R.T., S.D., R.B., M.F.D.C.), and Division of Cardiovascular Medicine, Department of Medicine (V.L.M., V.R.T., J.H., S.D., R.B., M.F.D.C.), Brigham & Women's Hospital, Boston, MA; Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (C.R.F., M.G., J.H., S.D., M.F.D.C.), and Istituto di Bioimmagini e Fisiologia Molecolare (O.R.), Consiglio Nazionale delle Ricerche and Scientific Institute San Raffaele, Milan, Italy; Division of Cardiology, Vita Salute University and Scientific Institute San Raffaele, Milan, Italy (P.G.C.). mdicarli@partners.org.
Marcelo F
MF
Di Carli
D000368:Aged; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging* / Q000453:epidemiology* / Q000401:mortality; D003326:Coronary Circulation; D016757:Death, Sudden, Cardiac / Q000453:epidemiology; D005260:Female; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000401:mortality; D006801:Humans; D008297:Male; D008833:Microcirculation; D055806:Microvessels / Q000000981:diagnostic imaging*; D008875:Middle Aged; D015999:Multivariate Analysis; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000453:epidemiology; D055414:Myocardial Perfusion Imaging; D049268:Positron-Emission Tomography; D015995:Prevalence; D012307:Risk Factors; D017678:Sex Distribution; D016896:Treatment Outcome; D061205:Vascular Calcification / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000401:mortality
atherosclerosis; blood flow velocity; microcirculation; sex; women