Coronary slow flow (CSF) may be a reflection of a systemic slow-flow phenomenon in the coronary arterial tree. In this study, the CSF group consisted of 24 men (77.4%) and 7 women (22.5%). An age- and gender-matched normal coronary artery (control) group was composed of 21 men (72.4%) and 8 women (27.5%). Retinal arteriovenous circulation time was measured using fundus fluorescein angiography as a part of the microcirculation and the circulation time between the antecubital vein and the retina as a part of the systemic circulation in patients with CSF and controls with normal coronary arteries. The mean arm-retina circulation time was 19.0 ± 5.7 seconds in the CSF group and 14.1 ± 3.1 seconds in the control group (p <0.001). The mean retinal arteriovenous passage time was 2.6 ± 0.9 seconds in the CSF group and 2.1 ± 0.7 seconds in the control group (p = 0.001). Strikingly, retinal findings of chronic central serous retinopathy were observed in 3 patients in the CSF group. In conclusion, CSF may indeed be a part of a systemic slow-flow phenomenon. The association of central serous retinopathy with this condition suggests that corticosteroids and the sympathetic system may play important roles in the pathogenesis of the disease by causing or contributing to increases in microvascular resistance and tonus.
The microvascular circulation in the retina can be observed directly and repeatedly, and minimal changes or anomalies can be detected by computer-supported retinal photographic imaging techniques. Current data have demonstrated a direct relation between retinal microvascular findings and clinical or subclinical cardiovascular, cerebrovascular, and metabolic events. Retinal vascular imaging provides information regarding the cumulative microcirculatory effects of an individual’s lifetime exposure to environmental or disease-related conditions, which may be modified by genetic predisposition. Retinal imaging has not yet been evaluated in patients with coronary slow flow (CSF). The present study was performed to evaluate the systemic circulation by measuring the time of circulation between the antecubital vein and the retina using fundus fluorescein angiography. Using this method, the effects of systemic diseases and the cumulative microvascular effects on the retina can be detected.
Methods
Thirty-one patients (the CSF group) with angina (stable or unstable) with risk factors and CSF detected on coronary angiography and 29 patients with normal coronary blood flow (the control group) were included in the study. Patients with cardiomyopathy, heart failure, coronary stenosis, left ventricular hypertrophy or dilation, atrial fibrillation, valvular or congenital heart disease, connective tissue disease, diabetes mellitus, thyroid function disorders, arrhythmia or bundle branch block, or chronic liver or kidney failure and those receiving nitrate therapy were excluded from the study. The same exclusion criteria were also applied to the control group.
The study was conducted according to the recommendations set by the Declaration of Helsinki on biomedical research involving human subjects. The institutional ethics committee approved the study protocol, and all patients and controls provided written informed consent. All patients underwent physical examinations, and their medical histories were taken. Cardiovascular risk factors, patients’ medications, and results of blood tests were recorded. Patients with systolic arterial pressure >140 mm Hg or diastolic arterial pressure >90 mm Hg on the basis of repeated measurements and those with histories of high blood pressure were defined as having hypertension. Patients with low-density lipoprotein levels >130 mg/dl and those who used statins were defined as having hyperlipidemia. Patients with triglyceride levels >150 mg/dl and those who used medications for high triglyceride levels were defined as having hypertriglyceridemia. Patients’ histories were checked for any type of allergic reactions before fundus fluorescein angiography. All subjects underwent vision examinations and measurements of ocular pressure. All patients underwent coronary angiography for the evaluation of chest pain.
Thrombolysis In Myocardial Infarction (TIMI) frame count was determined from coronary angiograms. In addition to the standard positions in coronary angiography, the caudal right anterior oblique approach was used to evaluate the left anterior descending coronary artery (LAD) and the left circumflex coronary artery, and the cranial left anterior oblique approach was used to evaluate the right coronary artery. Angiograms were evaluated by 2 different researchers. Mean values were calculated and accepted if there was little difference between the 2 measurements. The corrected TIMI frame count method of Gibson et al was used to analyze the movement of an opaque substance through the circulation and CSF samples. The corrected TIMI frame counts for filling and length of coronary arteries obtained were 36.0 ± 1.0 for the LAD, 22.2 ± 4.0 for the left circumflex coronary artery, and 20.4 ± 3.0 for the right coronary artery, as mean reference values. In the present study, 2 standard deviations above the mean were 38 for the LAD, 30 for the left circumflex coronary artery, and 26 for the right coronary artery, and values higher than these were accepted as indicating CSF. The images were acquired at 25 frames/second. Thus, to adjust for the 30 frames/second acquisition speed that was used in the original study by Gibson et al, a conversion factor of 1.2 was used to convert the frame rate values.
An intravenous catheter was inserted into the antecubital vein for fundus fluorescein angiography before the application of the mydriatic agent for patients with intraocular pressures <20 to 21 mm Hg as determined by tonometry. Retinal photographs were obtained using a Topcon IMAGEnet 2000 TRC-50 retinal camera (Topcon, Capelle aan den IJssel, The Netherlands) with the exclusion of red light. The video timer was started as 5 ml of 10% fluorescein sodium/70 kg was injected. The aim was to achieve a high concentration in the retina by rapid hand injections (1 to 2 seconds). Records were taken at 1-second intervals from the first entrance to the retina to the late venous phase. This lasted for 30 seconds, and late-phase photos were taken after an interval of 2 to 3 minutes.
Arm-retina time (ART) and arteriovenous passage (AVP) time were measured as retinal circulation parameters. The video fluorescein angiograms were enlarged and examined visually by 2 researchers. ART is described as the time between the administration of an opaque substance into the vein until it becomes visible in the retinal arteries. Normal mean values for ART have been reported as 9.0 to 21.5 seconds (mean 14.1) and 11.2 ± 3.3 seconds. In the present study, the measurement area was the edge of the optic disc. AVP time is the shortest time of retinal microcirculation and is the same as the early arteriovenous phase; it is described as the time period between the entrance of the opaque substance to the edge of the optic disc or to the retinal artery from a distance of 2 optic discs and the appearance of the opaque substance in the vein at the same point. Normal mean values for AVP time have been reported as 1.75 ± 0.5 seconds, 1.45 ± 0.4 seconds, 1.46 ± 0.57 seconds, and 3.5 ± 1.00 seconds. In the present study, measurements were obtained from the temporal region from an average distance of 2 optic discs.
SPSS for Windows version 11.5 (SPSS, Inc., Chicago, Illinois) was used for data analysis. The normality of the distributions for continuous variables was assessed using the Shapiro-Wilk test. Definitive statistics for continuous variables are expressed as mean ± SD or as median (range), and nominal values are given as the number of cases and as percentages. Significant differences in mean values between the groups were evaluated using Student’s t tests, and the significance of differences in median values between the groups was examined using Mann-Whitney U tests. The statistical significance of associations between the continuous variables was examined using Pearson’s and Spearman’s correlation tests. Variables obtained by univariate logistic regression analysis with p values <0.25 were accepted as candidate risk factors. The candidate risk factors were analyzed by multivariate logistic regression analysis, and p values <0.05 were considered statistically significant.
Results
Group demographics, symptoms, and findings of the cardiovascular system as well as laboratory findings are listed in Table 1 . Among the 31 patients, CSF was established only in the LAD in 13 patients (41.9%), in the LAD and left circumflex coronary artery in 10 patients (32.2%), in the LAD, left circumflex coronary artery, and right coronary artery in 6 patients (19.3%), in the left circumflex and right coronary arteries in 1 patient (3.2%), and in the right coronary artery in 1 patient (3.2%).
| Variable | CSF Group (n = 31) | Control Group (n = 29) | p Value |
|---|---|---|---|
| Men | 24 (77.4%) | 21 (72.4%) | 0.655 |
| Women | 7 (22.6%) | 8 (27.6%) | |
| Age (yrs) | 52.2 ± 6.9 | 49.9 ± 7.9 | 0.245 |
| Body mass index (kg/m 2 ) | 29.0 ± 3.4 | 28.1 ± 3.0 | 0.318 |
| Smokers | 22 (70.9%) | 16 (55.2%) | 0.205 |
| Smoking duration (pack-yrs) | 21.1 ± 10.2 | 14.3 ± 9.6 | 0.025 |
| Co-morbid disease ∗ | 9 (29.0%) | 4 (13.7%) | 0.213 |
| Family history of coronary artery disease | 13 (41.9%) | 3 (10.3%) | 0.008 |
| Systemic hypertension | 9 (29.0%) | 6 (20.7%) | 0.233 |
| Hyperlipidemia | 14 (45.2%) | 13 (44.8%) | 0.326 |
| Electrocardiographic changes † | 9 (29.0%) | 4 (13.8%) | 0.213 |
| Exercise testing (positive) | 9 (29.0%) | 8 (27.6%) | 1.000 |
| Unstable angina pectoris ‡ | 23 (74.2%) | 11 (37.9%) | 0.005 |
| Stable angina pectoris | 8 (25.8%) | 18 (62.1%) | 0.005 |
| Troponin (positive) § | 3 (10.0%) | 0 (0%) | 0.238 |
| Medications | |||
| β blockers | 9 (29.0%) | 7 (24.1%) | 0.668 |
| Angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers | 7 (22.6%) | 6 (20.6%) | 0.859 |
| Statins | 7 (22.6%) | 3 (10.3%) | 0.302 |
| Aspirin | 21 (67.7%) | 9 (31.0%) | 0.003 |
| Urgent coronary angiography | 8 (25.8%) | 0 (0%) | 0.005 |
| Hemoglobin (g/dl) | 14.7 ± 1.3 | 13.4 ± 1.4 | 0.002 |
| Thrombocytes (×10 3 /mm 3 ) | 237.1 ± 48.3 | 250.4 ± 53.6 | 0.520 |
| Low-density lipoprotein (mg/dl) | 127.2 ± 28.4 | 112.5 ± 18.5 | 0.063 |
| Triglycerides (mg/dl) | 168.9 ± 84.8 | 183.9 ± 74.7 | 0.280 |
| High-density lipoprotein (mg/dl) | 38.0 ± 9.29 | 41.69 ± 5.87 | 0.010 |
∗ In the CSF group: myotonic dystrophy in 1 patient, chronic obstructive pulmonary disease in 2 patients, alcohol addiction in 1 patient, familial Mediterranean fever in 2 patients, erectile dysfunction in 3 patients; in the control group: chronic obstructive pulmonary disease in 2 patients, depression in 2 patients.
† Rest electrocardiography ST-segment or T-wave abnormalities (transient ST-segment elevation >0.5 mm, transient or persistent ST-segment depression >0.5 mm, or definite T-wave inversion >1 mm).
‡ The Braunwald classification of unstable angina was used.
§ Troponin I level >0.01 ng/ml (Roche Elecsys, third generation; Roche Diagnostics GmbH, Mannheim, Germany).
There were significant differences in the corrected TIMI frame counts, ART, AVP time, and total circulation time between the CSF and control groups. These results are listed in Table 2 .
| Variable | CSF Group | Control Group | p Value |
|---|---|---|---|
| TIMI frame count | |||
| LAD | 48.2 ± 11.3 | 24.1 ± 5.1 | <0.001 |
| Left circumflex coronary artery | 39.1 ± 15.0 | 18.8 ± 3.9 | <0.001 |
| Right coronary artery | 24.7 ± 9.6 | 15.5 ± 3.5 | <0.001 |
| Mean | 37.3 ± 10.9 | 19.5 ± 3.6 | <0.001 |
| ART (seconds) | 19.0 ± 5.7 | 14.1 ± 3.1 | <0.001 |
| AVP time (seconds) | 2.6 ± 0.9 | 2.1 ± 0.7 | 0.001 |
| Total circulation (seconds) | 21.7 ± 6.1 | 16.2 ± 3.4 | <0.001 |
In the whole study group (n = 60), LAD, right coronary artery, left circumflex coronary artery, and mean TIMI frame counts were positively correlated with the measurements of ART, AVP time, and ART plus AVP time ( Table 3 ). There was a weak negative correlation between high-density lipoprotein and AVP time (r = −0.267, p = 0.040). Multivariate logistic regression analysis was performed to establish risk factors in predicting CSF. Increase in age, absence of hypertension, presence of chest pain at rest, and increase in hemoglobin were found to be significant risk factors for CSF ( Table 4 ).
| Factor | ART | AVP Time | ART Plus AVP Time | |||
|---|---|---|---|---|---|---|
| r | p | r | p | r | p | |
| Age | 0.071 | 0.591 | 0.037 | 0.779 | 0.078 | 0.552 |
| Body mass index | 0.191 | 0.144 | −0.082 | 0.534 | 0.140 | 0.285 |
| Low-density lipoprotein | 0.191 | 0.144 | 0.191 | 0.143 | 0.190 | 0.146 |
| High-density lipoprotein | −0.163 | 0.212 | −0.267 | 0.040 | −0.187 | 0.152 |
| Triglycerides | −0.102 | 0.436 | 0.087 | 0.508 | −0.077 | 0.558 |
| TIMI frame count | ||||||
| LAD | 0.577 | <0.001 | 0.492 | <0.001 | 0.598 | <0.001 |
| Left circumflex coronary artery | 0.620 | <0.001 | 0.543 | <0.001 | 0.645 | <0.001 |
| Right coronary artery | 0.600 | <0.001 | 0.393 | 0.002 | 0.605 | <0.001 |
| Mean | 0.633 | <0.001 | 0.517 | <0.001 | 0.653 | <0.001 |
| Hemoglobin | 0.200 | 0.125 | 0.168 | 0.200 | 0.207 | 0.112 |
| Platelets | −0.214 | 0.100 | −0.191 | 0.144 | −0.223 | 0.086 |
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