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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