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) |