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

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]