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Table 1 Characteristics of the included studies

From: Evaluation of non-invasive imaging parameters in coronary microvascular disease: a systematic review

Author (year) Study design Patient group N Mean age (± SD) Sex (F/M) Control group N Mean age (± SD) Sex (F/M) Imaging modality (outcome parameter) Vasoactive agent used (dose)
Meeder (1997) Case–control Patients with syndrome X with typical cardiac chest pain with exercise-induced ischemic-appearing electrocardiographic changes (> 1 mm horizontal ST-T segment depression) and/or reversible myocardial perfusion defects at thallium-201 perfusion scintigraphy and no significant CAD on CAG. Gastro-intestinal causes of chest pain were excluded 25 51 ± 9 16/9 Healthy volunteers 21 42 ± 13 8/13 PET (MPR), N-13 ammonia Dipyridamole (0.56 mg/kg per 4 min)
Bottcher (1999) Case–control Angina pectoris and positive stress ECG, normal CAG without risk factors for CAD 25 53 ± 7 25/0 Healthy age and sex matched volunteers 15 54 ± 10 15/0 PET (CFR), N-13 ammonia Dipyridamole (0.56 mg/kg per 4 min)
Buus (1999) Case–control Typical effort angina, positive stress ECG, normal CAG and TTE. No history of hypertension or diabetes mellitus 16 56.6 ± 1.2 13/3 Healthy subjects (recruited among blood donors and hospital staff) 15 53.5 ± 1.1 12/3 PET (CFR), N-13 ammonia Dipyridamole (0.56 mg/kg per 4 min)
Panting (2002) Case–control Typical effort angina, abnormal stress ECG, normal CAG recruited from Women’s Heart Disease Clinic at Royal Brompton Hospital (London) 20 55.9 ± 10.5 16/4 Healthy age and sex matched subjects, no history of chest pain and low cardiovascular risk profile. No SPECT or CAG was performed 10 57.9 ± 7.4 8/2 CMR (MPRI), 1.5 T Adenosine (140 mcg/kg/min for 6 min)
Marroquin (2003) Case–control Women with chest pain and epicardial coronaries that were angiographically normal or with only minimal luminal irregularities (< 50% stenoses) who were enrolled in the WISE study at the University of Pittsburgh 34 52.1 ± 10.0 34/0 Healthy age-matched women 9 50.4 ± 12.2 9/0 PET (CFR), 13-N ammonia Adenosine (140 mcg/kg/min for 4 min)
De Vries (2006) Case–control Typical chest pain and normal CAG. Exclusion: LBBB on ECG, first degree AV block and diabetes mellitus 42 58 ± 12 26/16 Healthy volunteers without chest pain or CAD 21 N/A N/A PET (CFR), N-13 ammonia Dipyridamole (0.56 mg/kg per 6 min)
Graf (2006) Case–control Typical angina, normal CAG and positive stress ECG or SPECT, exclusion of myocardial or valvular disease by TTE. Exclusion: diabetes mellitus 58 58 ± 10 39/19 N/A N/A N/A N/A PET (CFR), N-13 ammonia Dipyridamole (0.56 mg/kg per 4 min)
Pärkkä (2006) Cross-sectional/descriptive N/A N/A N/A N/A Male volunteers, nonsmoking. One patient with hypertension, others no history of cardiovascular disease 18 40.0 ± 14.4 0/18 CMR (MPR), 1.5 T
PET (MPR), 15O-labeled water
Dipyridamole (0.56 mg/kg per 4 min)
Wöhrle (2006) Case series Typical angina pectoris and normal CAG 12 61.8 ± 8.2 7/5 N/A N/A N/A N/A CMR (MPRI), 1.5 T Adenosine (140 mcg/min/kg for 3 min)
Galiuto (2007) Case–control Typical effort angina, positive stress ECG and normal CAG. Exclusion: moderate to severe hypertension, diabetes mellitus, other heart disease or contraindications to adenosine infusion 17 55 ± 10 9/8 Healthy subjects age and sex matched. Exclusion: moderate to severe hypertension, diabetes mellitus, other heart disease or contraindications to adenosine infusion 17 55 ± 10 10/7 TTE (CFR), distal LAD with pulse-wave Doppler Adenosine (140 mcg/kg in 90 s)
Graf (2007) Case–control Typical angina, normal CAG and positive stress ECG or SPECT. Myocardial or valve disease excluded by TTE. Exclusion: diabetes mellitus and other major diseases 79 58 ± 10 52/27 Atypical chest pain, normal CAG and negative stress test. Myocardial or valve disease excluded by TTE. Exclusion: diabetes mellitus and other major diseases 10 53 ± 11 6/4 PET (CFR), N-13 ammonia Dipyridamole (0.56 mg/kg per 4 min)
Vermeltfoort (2007) Case series Effort angina, positive stress ECG or SPECT and normal CAG. Exclusion: history of heart disease, hypertension, diabetes mellitus, absence of pain without medication, contra-indication for CMR 20 55 ± 11 15/5 N/A N/A N/A N/A CMR (MPRI), 1.5 T Adenosine (140 mcg/kg/min for 3 min)
Cemin (2008) Case–control N/A N/A N/A N/A Healthy volunteers with low pretest likelihood of coronary disease who were undergoing CAG 14 62.6 ± 9.1 8/6 TTE (CFR), distal LAD with pulse-wave Doppler Adenosine (140 mcg/kg/min for 5 min)
Lanza (2008) Case–control Effort angina, positive stress test and normal CAG. Exclusion: history of heart disease or systemic diseases 18 58 ± 7 11/7 Healthy volunteers, enrolled from the non-medical hospital staff, comparable in age and sex 10 54 ± 8 6/4 TTE (CFR), mid-distal LAD with Doppler spectral tracing Adenosine (140 mcg/kg/min for 90 s)
Di Monaco (2009) Case–control Patients presenting with effort angina, positive stress test and normal CAG in a university hospital. Exclusion: previous enrollment in SPECT study 29 59 ± 7 18/11 Healthy subjects, age and sex matched 20 56 ± 6 12/8 TTE (CFR), mid-distal LAD with Doppler spectral tracing Adenosine (140 mcg/kg/min for 90 s)
Mehta (2011) RCT Women with chest pain and abnormal stress testing, no obstructive CAD (< 50%) on CAG. Exclusion: renal failure or hepatic insufficiency, contraindication to withholding nitrates, calcium channel agents and beta-adrenergic blockers for 24 h, contraindication to CMR and use of drugs inhibiting CYP3A 20 57 ± 11 20/0 N/A N/A N/A N/A CMR (MPRI), 1.5 T Adenosine (140 mcg/kg/min for 5 min)
Scholtens (2011) Case–control Patients submitted for PET analysis because of typical chest pain, positive stress ECG and normal CAG 14 55 (34–76) Median (range) 10/4 Healthy subjects 13 58 (48–73) Median (range) 11/2 PET (MPR), N-13 ammonia Adenosine (140 mcg/kg/min for 6 min)
Sestito (2011) Case–control Patients with a history of effort angina, positive stress test and normal CAG undergoing clinical follow-up. Exclusion: other cardiac or systemic disease 71 56 ± 9 48/23 Healthy volunteers enrolled from the nonmedical hospital staff, age and sex matched 20 52 ± 7 11/9 TTE (CBF), mid-distal LAD with Doppler spectral tracing Adenosine (140 mcg/kg/min for 90 s)
Vaccarino (2011) Cohort N/A N/A N/A N/A Middle aged male-male twin pairs from the Vietnam Era Twin Registry without previous history of CAD 268 54.0 (53.5–54.6) Median (range) 0/268 PET (CFR), N-13 ammonia Adenosine (140 mcg/kg/min for 4 min)
Vermeltfoort (2011) Case series N/A N/A N/A N/A Healthy subjects without cardiovascular risk factors 27 41 ± 13 16/11 PET (CFR), 15O- labeled water Adenosine (140 mcg/kg/min for 3 min)
Di Franco (2012) Case–control Effort angina, positive stress test and normal CAG enrolled at outpatient ambulatory clinic 14 61 ± 5 9/5 Healthy subjects enrolled from patients referred to outpatient cardiology clinic for palpitations or evaluation of cardiovascular risk, age and sex matched 14 61 ± 3 7/7 TTE (CBF), mid-distal LAD with Doppler spectral tracing Adenosine (140 mcg/kg/min for 90 s)
Karamitsos (2012) Case–control Typical effort angina, abnormal stress ECG and normal CAG. Exclusion: diabetes mellitus, hypertension and other cardiac or systemic disease 18 62 ± 8 15/3 Healthy individuals without cardiovascular risk factors 14 58 ± 6 11/3 CMR (CFR), 3 T Adenosine (140 mcg/kg/min for 4–5 min)
Uusitalo (2013) Cohort N/A N/A N/A N/A Healthy men ≤ 45 years from healthy control groups of two earlies reported studies. Exclusion: hypertension, smoking, diabetes mellitus, obesity or history of atherosclerotic disease 77 35.3 ± 3.9 0/77 PET (CFR), 15O-labeled water Adenosine (dose not reported) or dipyridamole (0.56 mg/kg per 4 min)
Nelson (2014) Case–control N/A N/A N/A N/A Healthy age matched women with no cardiac risk factors 15 56 (SD not available) 15/0 CMR (MPRI), 1.5 T Adenosine (140 mcg/kg 3–4 min)
Thomson (2015) Case–control Women with signs and symptoms of ischemia with clinically indicated CRT; part of NHLBI-sponsored WISE-Coronary Vascular Dysfunction study performed at Cedars-Sinai Medical Center or the University of Florida. Exclusion: history of obstructive CAD (> 50% stenosis) or other cardiac disease, contraindications to CMR 118 53.9 ± 11.4 118/0 Healthy age matched women with no cardiac risk factors 21 53.6 ± 9.1 21/0 CMR (MPRI), 1.5 T Adenosine (140 mcg/kg from 2 min prior until completion of first pass perfusion imaging)
Tagliamonte (2015) RCT Signs and symptoms of myocardial ischemia, no CAD (< 70% stenosis on CAG). Myocardial ischemia confirmed by SPECT, assigned to placebo. Exclusion: renal failure or hepatic insufficiency, LBBB on ECG, use of drugs inhibiting CYP3A, other cardiac disease
As above, assigned to ranolazine
29
29
65 ± 11
66 ± 10
9/20
10/19
N/A N/A N/A N/A TTE (CFR), distal LAD with Doppler spectral tracing Dipyridamole (up to 0.84 mg over 6 min)
Wu (2015) RCT Diagnosis of CMD based on the presence of typical effort angina, exercise-induced ST segment depression (> 1 mm), normal CAG, absence of any specific cardiac disease including vasospastic angina and reduced CFR (< 2.0) measured by TTE with adenosine 20 60 ± 8 17/3 N/A N/A N/A N/A TTE (CBFVR), mid-distal LAD with Doppler spectral tracing Nitroglycerin (25 mcg)
Bairey Merz (2016) RCT Symptoms due to ischemia objectified by stress testing, no obstructive CAD (< 50% stenosis on CAG) with abnormal CRT (CFR < 2.5) or CMR (MPRI < 2.0). Exclusion: other cardiac disease or life expectancy < 4 years, contraindication for CMR or use of CYP3A4 inhibitors 128 55.2 ± 9.8 123/5 N/A N/A N/A N/A CMR (MPRI), 1.5 T Adenosine (not reported)
Bakir (2016) Case series N/A N/A N/A N/A Women without signs and symptoms of myocardial ischemia and absence of cardiovascular risk factors recruited at Cedars-Sinai Medical Center based on their age and hormone-use status to match CMD subjects in the WISE trial. Exclusion: contraindication to CMR or adenosine, renal disease 20 54 ± 9 20/0 CMR (MPRI), 1.5 T Adenosine (140 mcg/kg/min for 3–4 min)
Mygind (2016) Case series Women referred for clinically indicated CAG due to angina-like chest pain form the Patient Analysis & Tracking System in eastern Denmark. Inclusion: CAD < 50% stenosis. Exclusion: other cause of chest pain more likely, no cardiac disease, life-expectancy < 1 year 963 62.1 ± 9.7 963/0 N/A N/A N/A N/A TTE (CFVR), LAD with pulsed-wave Doppler Contrast (SonoVue) used in case of difficulty visualizing LAD Dipyridamole (0.84 mg/kg in 6 min)
Anchisi (2017) Case series Recurrent chest pain, ECG alterations at ergometry and normal CAG. Exclusion: other cardiac disease and previous revascularization. Setting: Cardiology Unit of Azienda Ospedaliera-Universitaria ‘Maggiore della Carità’ in Novara 16 64 ± 11 10/6 N/A N/A N/A N/A TTE (CFR), color Doppler flow mapping, mid-distal LAD Dipyridamole (0.84 mg/kg per 6 min)
Jaarsma (2017) Case–control Typical effort angina, positive stress ECG and normal CAG (stenosis < 25%), consecutively enrolled at Maastricht University Medical Center. Exclusion: contraindications for CMR or adenosine. One patient excluded due to poor image quality 13 65 ± 9 7/6 N/A N/A N/A N/A CMR (MPR), 3 T Adenosine (140 mcg/kg/min for 4 min)
Michelsen (2017) Case–control Women with angina-like chest pain and no significant obstructive CAD (< 50% stenosis) and with successful TTE examination, randomly selected from the iPOWER study cohort 95
102
61.8 ± 8.8 (in all 107 particpants) 95/0
102/0
N/A N/A N/A N/A PET (MBFR), Rubidium-82; TTE (CFVR), LAD with pulse-waved Doppler; Contrast (SonoVue) used in case of difficulty visualizing LAD Adenosine (0.84 mg/kg per 6 min)
Dipyridamole (0.84 mg/kg per 6 min)
Liu (2018) Case–control Patients with angina and suspected or known CAD referred for outpatient diagnostic CAG without obstructive CAD on CAG 22 65 ± 8 8/14 Healthy age-matched subjects 20 61 ± 7 7/13 CMR (MPRI), 1.5 T or 3 T Adenosine (140 mcg/kg/min for ≥ 3 to 6 min)
Liu (2018) Case–control Patients with stable angina and suspected CAD referred for outpatient diagnostic CAG in a tertiary referral hospital with FFR ≥ 0.8 and IMR ≥ 25 U 13
11
N/A
N/A
N/A
N/A
Healthy volunteers 30 51 ± 15 9/21 CMR, 1.5 or 3 T Adenosine (140 mcg/kg/min, for ≥ 3 to 6 min)
Zorach (2018) Case–control Patients with typical effort angina and no CAD (< 50% stenosis) on CAG and with risk factors for CMD (diabetes mellitus or metabolic syndrome) recruited from the University of Virginia Health System 46 57.5 ± 11.2 34/12 Healthy controls without risk factors for CMD 20 53.4 ± 11.9 12/8 CMR (MPR), 1.5 T Regadenoson
Rahman (2019) Case–control Patients undergoing elective diagnostic angiography for investigation of exertional chest pain and nonobstructive coronary artery disease (< 30% diameter stenosis and/or fractional flow reserve > 0.80) with CFR < 2.5 38 2.01 ± 0.41 N/A Patients undergoing elective diagnostic angiography for investigation of exertional chest pain and nonobstructive coronary artery disease (< 30% diameter stenosis and/or fractional flow reserve > 0.80) with CFR > 2.5 27 2.68 ± 0.49 N/A CMR (MPR), 3 T Adenosine (140 mcg/kg/min for 3 min)
  1. CABG coronary artery bypass grafting, CAD coronary artery disease, CAG coronary angiography, CRT coronary reactivity testing, ECG electrocardiogram, F female, FFR fractional flow reserve, IMR index of microcirculatory resistance, ISMN isosorbide-5-mononitrate, LAD left anterior descending coronary artery, LBBB left bundle branch block, M male, NHLBI-sponsored WISE National Heart, Lung, and Blood Institute sponsored women’s ischemia syndrome evaluation, RCT randomized controlled trial