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Table 1 Summary of the human, animal and in vitro studies on the clinicopathology effects of substance use on the coronary microcirculation

From: Smoking, alcohol and opioids effect on coronary microcirculation: an update overview

Patient or animal model Study population Substance Administration duration/dose Clinical test/experiment Observed effect on coronary microcirculation References
Young healthy smokers 30 Cigarette Smoking Short-term chronic Positron emission tomography measuring myocardial perfusion during rest, cold stress and dipyridamole-induced hyperemia Impaired myocardial microcirculation function and regulation at cold stress (endothelial-dependent) [184]
Male healthy twins 360 Cigarette Smoking Chronic smokers Positron emission tomography measuring myocardial perfusion at rest and adenosine vasodilation Lowered CFR in smokers, even after adjusting for oxidative stress and inflammatory markers [185]
Inflammation markers: IL-6, CRP
Oxidative stress markers: hydroperoxides, GSH,/GSSG ratio
Healthy young male smokers 30 Cigarette Smoking Short-term chronic Positron emission tomography measuring Myocardial blood flow (MBF) at rest, adenosine and cold stress Reduced ratio of cold MBF to rest MBF (endothelium-dependent) [186]
Healthy smokers 19 Cigarette Smoking Chronic smokers Positron emission tomography measuring coronary flow reserve (CFR), before and after vitamin C administration Vitamin C restored CFR and the responsiveness of coronary microvessels [187]
Angina patients, female, no CAD 3568 Cigarette Smoking Chronic smokers Doppler echocardiography measuring coronary flow velocity reserve (CFVR) at rest and high dose dipyridamole Current smoking was identified as a predictor of impaired CFVR [188]
Vasospastic angina pectoris (VSA) patients 22 Cigarette Smoking Chronic smokers Doppler echocardiography measuring coronary flow reserve (CFR), at rest and adenosine administration Lowers CFR in smokers [189]
CAD patients 97 Cigarette Smoking Chronic smokers Coronary angiography measuring CFR, index of microcirculatory resistance (IMR), and fractional flow reserve (FFR); at rest and adenosine-induced hyperemia Higher IMR in current smokers, no difference in CFR or FFR [190]
Healthy young volunteers 20 Cigarette smoking Chronic and acute effect (chronic smokers with 4 h abstinence, smoking 2 cigarettes) Doppler echocardiography measuring coronary flow velocity (CFV), and coronary vascular resistance index (CVRI) No difference in CFR and CVRI at baseline, lower CFR and higher CVRI after smoking 2 cigarettes [191]
Healthy young volunteers 20 Cigarette smoking Acute (2 cigarette) Doppler echocardiography measuring coronary flow reserve (CFR) Similar reduction in CFR after light and regular cigarette smoking [192]
Healthy young smokers 62 Cigarette smoking Chronic and acute effect of light cigarette smoking vs. regular cigarette smoking Doppler echocardiography measuring coronary flow velocity reserve (CFVR) Both chronic and acute effects of regular and light cigarettes were similar, reducing the CFVR [193]
Healthy smokers 21 Cigarette smoking Acute, cigarettes with either > 1 mg, or < 1 mg nicotine content Doppler echocardiography measuring coronary flow reserve (CFR) Reduced CFR only in group smoking > 1 mg content cigarettes [194]
Healthy smokers 51 Cigarette smoking Chronic Measuring plasma and urine biomarkers of inflammation ( IL-6, IL-8, ILβ1 and TNFα), endothelial injury (Intracellular adhesion molecule 1, metalloproteinase-9) and oxidative stress (myeloperoxidase, 8-isoprostane) Biomarkers of inflammation, oxidative stress, immunity and tissue injury were increased in smokers [195]
Human coronary arterioles (HCAs) - Cigarette Smoking Chronic smokers Dissected human coronary arterioles obtained from cardiac surgery; reactivity and responsiveness of microcirculation was tested by video microscopy Smoking impaired Na+/K+ ATPase mediated vasodilation [196]
PCI patients 2765 Cigarette Smoking Chronic current or past smokers Health related quality of life(HRQOL) and disease specific health status analyzed by questionnaires Better cardiac health related outcomes in non-smokers and past smokers, compared to current smokers [119]
Alcoholic patients expired for advanced liver disease, with no CAD symptoms 18 EtOH Chronic (alcoholic) Histology of endomyocardial biopsies Endothelial cell degeneration, small lumen size, thickened micro-vessel walls with edema, perivascular fibrosis, vascular, subendothelial humps, and vascular wall inflammation [129]
Rat model 21 animals in each test group EtOH Chronic, 36% ethanol containing diet (4 weeks) Histology Thickened walls of micro-vessels and smaller lumen size, increased endothelial proliferation [121]
Rabbit model 10 animals per group EtOH Chronic ( diet containing 20% ethanol) 3 weeks Histology and ultra-structural analysis of the myocardium and cardiac capillaries Increased numerical density of the micro-vessels [120]
Alcoholic patients 40 EtOH Chronic (alcoholic patients) Histopathology analysis on cardiac biopsies obtained Increased capillary density with enhanced endothelial proliferation [122]
C57BL/6 J mice 7 animals per group EtOH Chronic (diet containing 36% ethanol) 12 weeks Histology Remodeling of the microcirculation, capillaries with widened peri-capillary distances [125]
Rats preconditioned before myocardial infarction induction 8 animals per group EtOH Chronic (preconditioned with low-dose ethanol (0.5 g/kg/day), high-dose ethanol (5 g/kg/day) of alcohol 4 weeks before MI induction Immunohistochemistry High dose: endostatin increased, no change in VEGF [126]
Low dose: increased VEGF, lowered endostatin
Cultured small-vessel murine endothelial cells 4–10 (SVEC4-10) - EtOH Acute, 100 mg/dl In vitro angiogenesis assay, Endothelial cell tube formation assay Impaired angiogenesis and reduction in VEGF receptors [127]
Yorkshire swine 14 EtOH Chronic 7 weeks after MI induction, 90 ml ethanol daily, Dissected micro-vessels /vasodilator response and histopathology analysis Increased angiogenesis, improved microvascular reactivity, endothelial function and myocardial perfusion in the ischemic regions of the myocardium [155]
Yorkshire swine 16 EtOH Chronic, 90 ml ethanol daily, 7 weeks Dissected micro-vessels /vasodilator response and histopathology analysis Increased capillary density, increased VEGF, no change in microvessel reactivity and myocardial perfusion [156]
Coronary artery vascular smooth muscle cells   EtOH Acute, 10–20 mM protein and mRNA analysis Increased VEGF [166]
Human umbilical vein endothelial cells (HUVECs)   EtOH Acute, 24 h, 1–100 mM Matrigel network formation assay, proliferation and migration assay, protein and mRNA analysis Activation of CBF-1/RBP-Jk mediated angiogenesis [23]
Human coronary artery endothelial cells (HCAECs) - EtOH Acute, 24 h, 1–50 mM Matrigel network formation assay, protein and mRNA analysis Activation of Flk-1/Notch mediated angiogenesis [24]
Rat model 26 EtOH Chronic, 3–24 month age, 12% in drinking water mRNA extraction from left ventricles of the heart, qRT-PCR Higher expression of p53 [23]
Patients with chest pain, positive ETT, normal angiography 250 Opium Chronic (addicted patients) Coronary angiography Opium addicted patients are more likely to develop CMD [24]
Patients with CAD, scheduled to undergo coronary artery bypass grafting surgery 35 Opioid-based anesthetic (fentanyl) Acute anesthetic dose of fentanyl up to 5 mg kg-1, 30 min) Vascular occlusion testing (VOT) and near-infrared spectroscopy Impaired coronary microvascular reactivity [156]
Cultured cells: mouse endothelial cells and cardiac myocytes - Morphine 1–100 ng/ml Biomolecular tests for analysis of VEGF expression (qPCR, ELISA) Reduced VEGF expression by cardiomyocytes and endothelial cells [166]