|Year : 2016 | Volume
| Issue : 1 | Page : 1-6
Role of endothelial function in coronary slow-flow phenomenon with angiographically normal coronaries
Department of Cardiology, Guntur Medical College, Guntur, Andhra Pradesh, India
|Date of Web Publication||18-Mar-2016|
Department of Cardiology,Guntur Medical College, Guntur,Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Background: Coronary slow flow phenomenon (CSFP) is not a benign phenomenon and has been associated with recurrent angina and sudden cardiac death but its etiopathogenesis remains unclear.
Aims and Objectives: To evaluate the role of endothelial function in patients with coronary slow flow (CSF) and to compare them with patients with normal coronary flow.
Methods: Fifty (n = 50) patients >18 years of age who presented with history of angina and whose coronary angiogram revealed normal epicardial coronaries with slow flow were included in the study. Fifty patients who presented with chest pain with normal epicardial coronaries and normal flow were taken as controls.
Results: There were no major differences in terms of mean age, sex distribution, prevalence of hypertension, diabetes, smoking status, lipid profile, haemoglobin, blood glucose, serum creatinine levels in between the two study groups ([Table 1]). A significant difference was found in the hs-CRP levels between the two groups (5.52 + 3.03 vs. 2.98 + 1.48 mg/L, P < 0.0001). CIMT was found to be significantly more in patients with CSF group than that in patients with normal coronary arteries and normal coronary flow (NCF group) (0.058 + 0.007 cm vs. 0.0045 + 0.005 cm, P < 0.0001). Percentage of endothelial dependent dilatation in patients with CSF group was significantly lesser than in NCF group (2.78 ± 0.10% compared with 6.11 ± 0.10%, P < 0.01). The percentage of nitroglycerine (NTG)-induced dilatation was not significantly different between patients with SCF and patients with NCF (7.4 + 1.1% compared with 8.1 ± 1.0%, P = 0.87).
Conclusion: Coronary slow flow phenomenon is a marker of atherosclerosis (as documented by carotid intima media thickness) and our study has also shown that endothelial function is significantly impaired in patients with coronary slow flow (as documented by impaired endothelial dependent vasodilatation) than that of patients with normal epicardial coronaries with normal flow.
Keywords: Atherosclerosis, slow flow, carotid intima media thickness
|How to cite this article:|
Nathani S. Role of endothelial function in coronary slow-flow phenomenon with angiographically normal coronaries. J NTR Univ Health Sci 2016;5:1-6
|How to cite this URL:|
Nathani S. Role of endothelial function in coronary slow-flow phenomenon with angiographically normal coronaries. J NTR Univ Health Sci [serial online] 2016 [cited 2019 May 21];5:1-6. Available from: http://www.jdrntruhs.org/text.asp?2016/5/1/1/178941
| Introduction|| |
Coronary slow-flow phenomenon (CSFP) is characterized by delayed opacification of coronary vessels in a normal coronary angiogram.  Although, myocardial biopsy studies have demonstrated the presence of coronary microvascular disease in some patients exhibiting coronary slow-flow, the phenomenon has not been extensively studied. It is not a benign phenomenon and has been associated with recurrent angina and sudden cardiac death. Till date, only a few small studies have been done to assess the CSFP. However, these studies have not evaluated comprehensively. The present study assesses clinical, biochemical, electrocardiographic, and echocardiographic parameters in patients with CSFP.
| Materials and methods|| |
The present study was a prospective study taking patients who underwent coronary angiogram with normal epicardial coronaries and slow-flow as subjects and patients with normal epicardial coronaries with normal flow were taken as controls.
Fifty (n = 50) patients >18 years of age, who presented with a history of angina and whose coronary angiogram revealed normal epicardial coronaries with slow-flow were included in the study. Fifty matched patients with normal epicardial coronaries with normal flow were taken as controls. Patients with slow-flow in all the coronary arteries were included.
CSFP is an angiographic finding characterized by Thrombolysis in Myocardial Infarction (TIMI)-2 flow in the absence of significant large vessel coronary disease. Presence or absence of slow-flow was decided by a single experienced operator.
Patients with slow-flow phenomenon were assessed:
- Patients with severe anemia, leukopenia, bleeding diathesis.
- Patients with liver disease (increased liver enzymes).
- Patients with deranged renal function. [serum creatinine (s. creatinine) >2.5 mg%]
- Patients with acute decompensated heart failure.
- Clinically, (age, sex, presence or absence of hypertension, diabetes, dyslipidemia, smoking habit).
- Biochemically, [lipid profile, high sensitive C-reactive protein (hs-CRP), blood sugar].
- Electrocardiographically, by treadmill test.
- By echocardiogram (left ventricular hypertrophy, systolic function, and diastolic function).
- By ultrasonogram, for carotid intimal medial thickness (CIMT).
- By brachial artery hyperemic studies for assessment of endothelial function and to compare it with that of healthy subjects.
Written informed consent was obtained from all of the individuals. Blood sampling was performed in the morning of the examination, after a 12-h overnight fast, to measure the hemoglobin, serum lipid profile, and other biochemical parameters. Serum total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride concentrations were measured enzymatically. Plasma glucose concentration [both fasting blood sugar (FBS) and random blood sugar (RBS), in case of diabetic subjects, and either one, in case of nondiabetic subjects] was assayed by the glucose oxidase method. For each participant, measurement of carotid intima-media thickness and brachial artery flow-mediated vasodilation (FMD) was performed to assess vascular endothelial function.
Brachial endothelial function test
After baseline measurements of brachial artery diameter, a blood pressure cuff was inflated on the proximal portion of the arm to 200 mm Hg for 5 min, creating distal limb ischemia. After release of the cuff, reactive hyperemia occurred, that is, flow in the brachial artery increased to accommodate the dilated resistance vessels in the forearm. The brachial artery was imaged for the first 2 min of reactive hyperemia. The flow-mediated dilator response was used as a measure of endothelium-dependent vasodilatation. Then, 15 min later, a further resting scan was recorded to confirm vessel recovery. Sublingual nitroglycerin (NTG) (0.4 mg) was then administered and 3-4 min later, the last scan was performed. The response to NTG is a measure of endothelium-independent vasodilatation.  The end point was the percent diameter change of the brachial artery in response to reactive hyperemia or NTG [Figure 1]a-c.
|Figure 1: (a) Baseline brachial artery diameter (b) Brachial artery diameter showing reactive hyperemia suggestive of endotheliumdependent dilatation (c) Brachial artery diameter showing endothelium-independent dilatation following sublingual nitroglycerin|
Click here to view
Measurement of circulating high sensitive C-reactive protein concentration
Blood samples were taken in the morning of the examination, after a 12-h overnight fast, to measure the serum hs-CRP concentration and these were collected in tubes containing citric acid and centrifuged immediately. All measurements were performed by automatic immunonephelometer with a lower detection of 0.0175 mg/dL.
The normal range of CRP was accepted as <3 mg/L. ,
Echocardiographic evaluation was made just before the angiographic study by Philips Sonos 5500 with a S-5 probe (Philips Electronics, NA). Echocardiography was performed in the left lateral decubitus position. All the measurements were performed according to the guidelines of the American Society of Echocardiography. Two-dimensional (2D) echocardiography and the modified Simpson's rule were used to determine ejection fraction (EF), left ventricular end-diastolic diameter, and left ventricular end-systolic diameter. Mitral flow velocity was obtained from the apical four-chamber view with the pulsed-wave technique by placing the sample volume between the tips of the mitral leaflets for conventional diastolic parameters of the left ventricle. The following parameters were calculated: Maximal velocity of early diastolic filling (E), maximal velocity of atrial diastolic filling (A), the ratio of maximal early to late diastolic filling (E/A), and deceleration time (DT).
Carotid artery ultrasonography
Carotid intimal thickness was determined using a high resolution ultrasound system Philips Sonos 5500 equipped with a 11-3 L MHz transducer. Longitudinal scans were done and the measurements were obtained in the middle of the common carotid artery (CCA). Three measurements of CIMT were measured for the left and right CCA and these values were averaged to obtain the mean CIMT [Figure 2].
|Figure 2: Ultrasonic image of common carotid artery of a patient with slow coronary flow|
Click here to view
An exercise test was done with a Mortara instrument using modified Bruce protocol.
For comparing the statistical significance of categorical variables (such as gender), the Pearson's chi-square test was applied. For determining the statistical significance of quantitative variables (such as age, sex, etc.), the Students t-test was applied. In case of quantitative variables that do not follow a normal distribution, nonparametric Wilcoxon-Mann-Whitney test was applied. For comparing the statistical significance of quantitative variables over a different time, nonparametric Wilcoxon signed-rank test was applied. The P value of <0.05 was considered as the level of statistical significance. Data was analyzed by using Statistical Package for the Social Sciences (SPSS) statistical software version 12 for windows (SPSS Inc., Chicago, IL).
| Results|| |
A total of 100 patients were enrolled; 50 patients in the study group and 50 patients in the control group. There were no major differences in terms of mean age, sex distribution, prevalence of hypertension, diabetes, smoking status, lipid profile, hemoglobin, blood glucose, and serum creatinine levels in between the two study groups [Table 1]. Stress testing with treadmill test was not significant between the two groups (P value of 0.658 for positive test between cases and controls) as well. Echocardiography showed that there were no significant differences in systolic and diastolic abnormalities between the two study groups. Serum hs-CRP concentration was significantly higher in the slow-flow group than that of controls (5.52 + 3.03 versus 2.98 + 1.48 mg/L, P < 0.0001). CIMT was significantly higher in the slow-flow group than that of controls (0.058 ± 0.007 versus 0.0045 ± 0.005 cm, P < 0.0001) [Table 2]. Mean percentage rise of brachial artery diameter with endothelium-dependent dilatation compared to baseline in cases is 4.27, whereas the mean percentage rise of brachial artery diameter with endothelium-dependent dilatation compared to baseline in controls is 20.56. P value for endothelium-dependent dilatation is statistically significant (0.0001), whereas there is no significant difference in the mean percentage rise of brachial artery diameter with endothelium-independent dilatation between the two groups (P value = 0.295, mean values being 18.64 and 20.48 for cases and controls, respectively) [Figure 3].
|Figure 3: Bar diagram showing percentage rise of brachial artery diameter of a patient with slow coronary flow when compared to baseline|
Click here to view
| Discussion|| |
Slow coronary flow (SCF) with normal epicardial arteries is still not a fully understood clinical phenomenon. It is often considered as an incidental angiographic finding; however, small clinical series and individual case reports have shown that it might cause angina pectoris, myocardial ischemia, and even myocardial infarction. ,,, The role of inflammation in the pathogenesis of SCF has been suggested by our findings of serum hs-CRP concentration that is increased in patients with SCF as compared to those with normal coronary flow (NCF). CRP may act as a procoagulant, as it is known to induce the expression of tissue factor in monocytes, and is additionally found in the vessel wall, even in the very early stages of plaque formation.  It induces complement activation and may enhance tissue injury via this mechanism.  In addition, it is involved in cellular adhesion molecule shedding, and finally, a strong association between increased plasma CRP and impaired endothelial function has been demonstrated recently. 
The CIMT is the best known sonographic marker for early atherosclerotic vascular wall lesions.  Previous cross-sectional studies in different populations have shown that increase in CIMT is associated with cardiovascular event prevalence. ,,,,,, Ahmet Camsari et al.  had shown that CIMT was significantly higher in the slow-flow group than that of controls (0.84 ± 0.14 versus 0.66 ± 0.13, P < 0.0001). Our study has shown similar findings (0.058 + 0.007 versus 0.0045 + 0.005 mg/L, P < 0.0001). Assessment of FMD of the brachial artery has been widely used as a simple and noninvasive method of determining endothelial function.  Recently, it has been shown that FMD is reduced in patients with coronary risk factors ,,,, and that FMD correlates with invasive testing of coronary endothelial function as well as severity and extent of coronary atherosclerosis. Sezgin et al., had shown that FMD in the participants with SCF was significantly smaller in those with NCF (3.48 ± 0.10% compared with 9.11 ± 0.10%, P < 0.001). The percentage of NTG-induced dilatation was not significantly different between participants with SCF and those with NCF (16.8 ± 1.1% compared with 17.1 ± 1.1%, P = 0.87). Our study has shown similar findings.
Regarding echocardiography techniques, tissue Doppler was not used, which is more sensitive than conventional 2D echocardiography in identifying diastolic abnormalities. Measurements obtained were not blinded and it was a retrospective study.
| Conclusion|| |
In conclusion, the present study has shown that patients with coronary slow-flow have:
Thus, CSFP is a marker of atherosclerosis (as documented by carotid intimal media thickness) and our study has additionally shown that endothelial function is significantly impaired in patients with coronary slow-flow (as documented by impaired endothelium-dependent vasodilatation) than that of patients with normal epicardial coronaries with normal flow.
- Significantly higher levels of hs-CRP,
- Greater CIMT and
- Significantly impaired endothelium-dependent vasodilatation compared to control.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Beltrame JF, Limaye SB, Horowitz JD. The coronary slow flow phenomenon - A new coronary microvascular disorder. Cardiology 2002;97:197-202.
Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D, et al.
Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol 1995;26:1235-41.
Tracy RP, Lemaitre RN, Psaty BM, Ives DG, Evans RW, Cushman M, et al
. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly: Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol 1997;17:1121-7.
Macy EM, Hayes TE, Tracy RP. Variability in the measurement of C-reactive protein in healthy subjects: Implications for reference intervals and epidemiological applications. Clin Chem 1997;43:52-8.
Kapoor A, Goel PK, Gupta S. Slow coronary flow-a cause for angina with ST segment elevation and normal coronary arteries. A case report. Int J Cardiol 1998;67:257-61.
Przybojewski JZ, Becker PH. Angina pectoris and acute myocardial infarction due to "slow-flow phenomenon" in nonatherosclerotic coronary arteries: A case report. Angiology 1986;37:751-61.
César LA, Ramires JA, Serrano Júnior CV, Meneghetti JC, Antonelli RH, da-Luz PL, et al
. Slow coronary run-off in patients with angina pectoris: Clinical significance and thallium 201 scintigraphic study. Braz J Med Biol Res 1996;29:605-13.
Legrand V, Hodgson JM, Bates ER, Aueron FM, Mancini GB, Smith JS, et al
. Abnormal coronary flow reserve and abnormal radionuclide exercise test results in patients with normal coronary angiograms. J Am Coll Cardiol 1985;6:1245-53.
Torzewski J, Torzewski M, Bowyer DE, Fröhlich M, Koenig W, Waltenberger J, et al
. C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries. Arterioscler Thromb Vasc Biol 1998;18:1386-92.
Fichtlscherer S, Rosenberger G, Walter DH, Breuer S, Dimmeler S, Zeiher AM. Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation 2000;102:1000-6.
Kasliwal RR, Bansal M, Bhargava K, Gupta H, Tandon S, Agrawal V. Carotid intima-media thickness and brachial-ankle pulse wave velocity in patients with and without coronary artery disease. Indian Heart J 2004;56:117-22.
Burke GL, Evans GW, Riley WA, Sharrett AR, Howard G, Barnes RW, et al
. Arterial wall thickness is associated with prevalent cardiovascular disease in middle-aged adults. The Atherosclerosis Risk in Communities (ARIC) Study. Stroke 1995;26:386-91.
Kronmal RA, Smith VE, O'Leary DH, Polak JF, Gardin JM, Manolio TA. Carotid artery measures are strongly associated with left ventricular mass in older adults (a report from the Cardiovascular Health Study). Am J Cardiol 1996;77:628-33.
Mattace Raso F, Rosato M, Talerico A, Cotronei P, Mattace R. Intimal-medial thickness of the common carotid arteries and lower limbs atherosclerosis in the elderly. Minerva Cardioangiol 1999;47:321-7.
Mannami T, Baba S, Ogata J. Strong and significant relationships between aggregation of major coronary risk factors and the acceleration of carotid atherosclerosis in the general population of a Japanese city: The Suita study. Arch Intern Med 2000;160:2297-303.
Hodis HN, Mack WJ, LaBree L, Selzer RH, Liu CR, Liu CH, et al
. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med 1998;128:262-9.
Chambless LE, Heiss G, Folsom AR, Rosamond W, Szklo M, Sharrett AR, et al
. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: The atherosclerosis risk in communities (ARIC) study, 1987-1993. Am J Epidemiol 1997;146:483-94.
Newman AB, Naydeck B, Sutton-Tyrrell K, Edmundowicz D, Gottdiener J, Kuller LH. Coronary artery calcification in older adults with minimal clinical or subclinical cardiovascular disease. J Am Geriatr Soc 2000;48:256-63.
Camsari A, Ozcan T, Ozer C, Akcay B. Carotid artery intima-media thickness correlates with intravascular ultrasound parameters in patients with slow coronary flow. Atherosclerosis 2008;200:310-4.
Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, et al
. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111-5.
Sorensen KE, Celermajer DS, Georgakopoulos D, Hatcher G, Betteridge DJ, Deanfield JE. Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein (a) level. J Clin Invest 1994;93:50-5.
Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O, Robinson J, et al
. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilatation in healthy young adults. Circulation 1993;88:2149-55.
Celermajer DS, Sorensen KE, Bull C, Robinson J, Deanfield JE. Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction. J Am Coll Cardiol 1994;24:1468-74.
Zeiher AM, Drexler H, Saurbier B, Just H. Endothelium-mediated coronary blood flow in humans: Effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest 1993;92: 652-62.
Hashimoto M, Kozaki K, Eto M, Akishita M, Ako J, Iijima K, et al
. Association of coronary risk factors and endothelium-dependent flow-mediated dilatation of the brachial artery. Hypertens Res 2000;23:233-8.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]