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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 9  |  Issue : 1  |  Page : 39-44

The relation of brachial fractional flow dilatation and coronary artery disease in nondiabetic patients with or without insulin resistance


1 Department of Cardiology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 National Research Centre, Cairo, Egypt

Date of Web Publication10-May-2019

Correspondence Address:
Dr. Wael Ali Khalil
Department of Cardiology, Faculty of Medicine, Zagazig University, Zagazig
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JICC.JICC_3_18

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  Abstract 


Background: Endothelial dysfunction is the early sign of cardiovascular diseases and assessed by the flow-mediated dilatation (FMD) of the brachial artery. In patients with insulin resistance, endothelial dysfunction is reduced and assessed by FMD. The work aimed to study the association between (homeostatic model assessment of the insulin resistance) and the brachial fractional flow dilatation (FFD) with the presence of coronary artery disease (CAD) in nondiabetic individuals, with or without insulin resistance. Patients and Methods: A total of 100 nondiabetic individuals were following up in the cardiology department and divided into (Group 1) 40 patients with insulin resistance (Group 2). Sixty patients without insulin resistance. FMD of the brachial artery was measured then the nitroglycerin-mediated dilatation (NMD). We calculated the fractional flow dilatation (FFD) as follow: NMD-FMD/NMD. Results: The predictive value of FFD for the detection of CAD in insulin resistance group with a cutoff value >0.465 (P < 0.0001), with a sensitivity of 89.2% and specificity of 92.3%. The predictive value of FFD is ≥0.575 (P = 0.001), with a sensitivity of 78.9% and specificity of 74.2% in the non-IR group. Conclusion: FFD is independent predictors for CAD, especially in insulin resistance subjects.

Keywords: Endothelial dysfunction, insulin resistance, the fractional flow dilatation


How to cite this article:
Khalil WA, AbdElsalam R, Abdou M, Hamed A, Younnis K. The relation of brachial fractional flow dilatation and coronary artery disease in nondiabetic patients with or without insulin resistance. J Indian coll cardiol 2019;9:39-44

How to cite this URL:
Khalil WA, AbdElsalam R, Abdou M, Hamed A, Younnis K. The relation of brachial fractional flow dilatation and coronary artery disease in nondiabetic patients with or without insulin resistance. J Indian coll cardiol [serial online] 2019 [cited 2019 Sep 17];9:39-44. Available from: http://www.joicc.org/text.asp?2019/9/1/39/257957




  Introduction Top


The cardiovascular diseases are one of the leading causes of morbidity and mortality worldwide.[1] The cardiovascular many risk factors have been present for many years before clinical atherosclerosis becomes evident.[2] Insulin resistance is leading to many cardiovascular hazards such as endothelial dysfunction, coronary artery disease (CAD), and hypertension.[3] Systemic insulin resistance is a pathological state in which there is a loss of cell response to insulin hormone actions. This may lead to a subnormal response to the normal insulin concentrations with subsequent increase of insulin production by B cells of the pancreas (hyperinsulinemia) and increased blood sugar level (hyperglycemia), which produces a proatherogenic lipid phenotype by increasing (very low-density lipoprotein [LDL]) particles and initiation of pro-inflammatory and pro-coagulant states in the process of atherosclerosis.[4],[5] The homeostatic model assessment of the insulin resistance (HOMA-IR) is a simple test for measuring insulin resistance depending on fasting blood insulin (FBI) and glucose levels.[6] It is also valuable for risk stratification in patients with angiographically documented CHD.[7] Endothelial dysfunction is the early sign of cardiovascular diseases and assessed by the flow-mediated dilatation (FMD) of the brachial artery. FMD is a simple, noninvasive technique used in diabetics and nondiabetics which is reduced in endothelial dysfunction especially in insulin resistance patients who have more endothelial dysfunction.[8],[9] Endothelial dysfunction proceeds by the reduction of the nitric oxide. A physical stimulus such as hypoxia could release nitric oxide from the endothelial cells.[10] FMD is a method for the measurement of the severity of vasodilatation in response to shear stress.[11] The work aimed to study the association between (HOMA-IR) index and the brachial fractional flow dilatation (FFD) with the occurrence of CAD in nondiabetic patients, with or without insulin resistance.


  Patients and Methods Top


One hundred nondiabetic individuals were following up in the cardiology department and divided into (Group I) 40 patients with insulin resistance (Group II). Sixty patients without insulin resistance.

Inclusion criteria

Age (30–60 years) with stable cardiac rhythm whose is complaining of typical chest pain suggestive of myocardial ischemia and all of them underwent coronary angiography for diagnosis of (CAD).

Exclusion criteria

Exclusion criteria include diabetes mellitus, acute coronary syndromes, unstable cardiac rhythm, and impaired renal function. This study was also approved by the International Review Board of the faculty of medicine, Zagazig University and all patients were included in the study after signing the informed consent form. All patients were subjected to all the following.

Complete history taking

With special emphasis on age, sex, risk factors including hypertension, diabetes mellitus, smoking, dyslipidemia, and history of CAD. Thorough physical examination including (pulse, blood pressure, neck veins, cardiac examination, and general examinations), resting 12-lead electrocardiogram (ECG) was done to detect changes suggestive of ischemia. Stress ECG was done for normal baseline ECG then included those with positive stress test in our study.

Laboratory investigations

Fasting and 2-h postprandial blood glucose level, serum insulin level for the assessment of insulin resistance, glycosylated hemoglobin (HbA1C), serum LDL, high-density lipoproteins (HDL) cholesterol, and serum triglycerides (TG).

Echocardiography

All patients underwent two-dimensional echocardiography during index hospitalization using GE vivid 9. Recordings and calculations of different parameters were performed according to the recommendations of the American Society of Cardiology focusing on the left ventricular (LV) systolic function, determined by ejection fraction percent, LV diastolic function, LV dimension, significant mitral regurgitation, and the presence of wall motion abnormalities. The cardiac catheterization was performed for all patients. The presence of CAD, the number of diseased vessels, and the percentage of stenosis in each vessel will be determined.

Measurement of flow-mediated dilatation of the brachial artery and calculation of the fractional flow dilatation

Is a simple, noninvasive test that used for the assessment of endothelial dysfunction and prediction of CAD depending on induction of a hyperemic blood flow stimulus post blood pressure cuff occlusion then release.

We measured FMD by using high-resolution ultrasound (Hewlett-Packard Sonos 5500) with a 7.5 MHz probe for evaluating the endothelial function. FMD was measured, in a dark, quiet room, in the early morning after at least 12 h of overnight fasting, avoiding vasoconstriction induced drugs such as sympathomimetics and nasal decongestants. At first, the brachial artery was defined by the ultrasound probe about 3–5 cm above the elbow. Then, the media to media distance of the brachial artery was measured at end diastole. After measuring the brachial artery baseline diameter, the blood pressure cuff was inflated to at least 50 mmHg above the systolic pressure at the upper arm for 5 min to cause the hyperemic blood flow stimulus. The media-to-media distance at the same brachial artery site was measured 1 min after release of the blood pressure cuff. We expressed The FMD as the percent change of the hyperemic brachial artery diameter relative to the baseline brachial artery diameter. After 20 min of rest, the brachial artery diameter was measured again to assess the baseline brachial artery diameter again. The brachial artery diameter was measured 5 min after the administration of 5 mg Sublingual nitroglycerin. We expressed Nitroglycerin-mediated dilatation (NMD) as the percentage change of the brachial artery diameter after nitroglycerine administration relative to the baseline brachial artery diameter. The FFD was then be calculated as follows: FFD (%) = NMD-FMD/NMD.

Statistical analysis

All data were collected and analyzed using SPSS (version 21). All data expressed as mean ± standard deviation. The correlation between variables was done. The statistical significance is considered at P < 0.05. Linear regression analysis was used to understand among the independent variables are related to the presence of CAD by cardiac catheterization. Multivariate analysis of variance was used to test the hypothesis that one or more independent variables influence the presence of CAD by cardiac catheterization. The cutoff values were estimated using the receiver operating characteristic (ROC) curve.


  Results Top


One hundred nondiabetic individuals came to the outpatient department of cardiology with typical chest pain suggestive of CAD with no history of premature CAD in all population. Divided into two groups according to insulin resistance: Insulin-resistant group (I) including 40 patients and noninsulin-resistant group (II) include 60 patients; all of them underwent coronary angiography and FFD of the brachial artery (FFD) assessment. In our study, as shown in [Table 1], there were 71 patients (71%) were male, 29 patients (29%) were female, their age ranged from 33 to 60 years with a mean of 50 ± 4.7 years. There were 40 patients (40%) hypertensive, 22 patients (22%) smokers, 58 patients (58%) with ischemic ECG changes, and 55 patients (55%) with CAD. There was a significant correlation between the presence of CAD evident by coronary angiography and the following parameters [Table 2]: ischemic ECG changes, blood insulin levels, HbA1c levels, HOMA test, insulin level, FFD, and CRP levels. There were no significant correlations between the presence of CAD evident by coronary angiography and the following parameters: age sex, hypertension, smoking, TG levels, and HDL levels. In the insulin-resistant group, there is a positive correlation between FFD and NTD, NMD, HOMA, insulin level, TG, and abdominal circumference. There is a negative correlation with hyperemic diameter and FMD. In noninsulin resistance group, there is a positive correlation between FFD and NTD, TG, abdominal circumference and there is a negative correlation between FMD and negatively correlated with FMD and hyperemic diameter. The value and accuracy of FFD % in predicting CAD in all patients, noninsulin resistance and insulin resistance groups with (cutoff value >10.9, >9.8, and >12.8%), sensitivity (98.3%, 95.1%, and 96.6%), specificity (88.4%, 84.3%, and 87.1%), and accuracy (94.7%, 90.3%, and 92.4%), respectively. The FFD is a more accurate test with more sensitivity, specificity, and accuracy for the prediction of CAD in all patients, insulin resistance and noninsulin resistance groups compared to FMD. The value and accuracy of FMD % in predicting CAD in all patients, noninsulin resistance and insulin resistance groups with (cutoff value <6.5, <7.4, and <6.1%), sensitivity (82.7%, 77.4%, and 81.2%), specificity (76.1%, 73%, and 75.3%), and accuracy (80.9%, 75.4%, and 79.1%) respectively are showing that FMD is less accurate test with less sensitivity and specificity for the prediction of coronary artery.
Table 1: The general characteristics of the all patients in two groups with and without insulin resistance

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Table 2: Different variables correlation with coronary artery disease diagnosed by coronary angiography in each group

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Linear regression analysis is showing that [Table 3]:
Table 3: Linear regression analysis of Group (I) and Group (II)

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Insulin-resistant group (I): The overall regression model was significant, indicating that FFD and HOMA-IR were unique variance predictors of CAD.

Noninsulin resistant group (II): The whole regression model was significant and showed that FFD, hypertension, and smoking were unique variance predictors of CAD.

The predictive value of FFD in the insulin-resistant group (I): ROC curve in insulin resistance group (I) is showing an excellent predictive value of FFD for prediction of CAD [Figure 1].
Figure 1: Receiver operating characteristic curve in insulin resistance group (i) showing an excellent predictive value of fractional flow dilatation for prediction of Coronary artery disease. The Predictive value of fractional flow dilatation in insulin resistant Group (i)

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  Discussion Top


Endothelial dysfunction proceeds over vascular disease by years and may itself be a potentially modifiable CVD risk factor.[12] Although no gold standard for the measurement of the endothelial function exists. The measurement of flow-mediated dilation (FMD) and FFD of the brachial artery assessed with Doppler ultrasonography are showing the most promising methods for clinical application. FFD is a new noninvasive test used in our study as a measure of endothelial dysfunction and depends on the flow-mediated diameter and nitroglycerin-mediated diameter of the brachial artery. We use the HOMA-IR as a practical and simple test for the assessment of insulin resistance.[13] We hypothesized that endothelial dysfunction measured by FFD is an independent predictor for CAD in nondiabetics especially in insulin-resistant subjects. We found in our study that FFD was positively correlated with CAD and other variables such as insulin resistance, HbA1c, blood insulin level, nitroglycerin-mediated diameter (NTD), high sensitivity CRP, blood pressure, fasting blood sugar (FBS), FBI level, abdominal circumference, and hypertriglyceridemia while negatively correlated with FMD and hyperemic diameter. No significant correlation between FFD and age, gender, ECG changes, echocardiographic findings, NMD, baseline diameter of the brachial artery, total cholesterol, LDL cholesterol, and HDL cholesterol. In our study, the insulin resistance is positively correlated with FFD, CAD, and other variables such as abdominal circumference, serum triglyceride, blood insulin level, HbA1c level, quantitative high sensitivity CRP, and FBS, while it was negatively correlated with FMD and hyperemic flow-mediated diameter. Our study has shown a significant association between insulin resistance and serum TG, obesity, hypertension, and hyperinsulinemia. This was in agreement with Katsuki et al. Who found a significant statistical relationship between insulin resistance and hypertension[14] Reaven and Chang who also found a significant statistical relationship between insulin resistance and obesity.[15] We did not find any significant statistical correlation between insulin resistance and LDL cholesterol, total cholesterol, and HDL cholesterol which was concordant with Katsuki et al.,[14] while we are discordant with Sandeep et al. who reported a statistically significant relationship between insulin resistance and total cholesterol, HDL cholesterol, and LDL cholesterol.[16] There was a significant association between insulin resistant and CAD, where the risk of CAD was 4.3 times higher in insulin-resistant subjects compared to noninsulin resistant (O. R = 4.3). Our study was in agreement with many prospective studies with little difference in the degree of risk, like; Suzuki et al. study in which the risk of CAD and other cardiovascular events was about three folds in insulin-resistant subjects compared to noninsulin resistant.[17] In insulin-resistance group, FFD was positively correlated with nitroglycerin-mediated diameter (NTD), HOMA-IR, FBS, blood insulin level, blood pressure, serum TG level, abdominal circumference and was negatively correlated with hyperemic diameter and FMD while in noninsulin resistance group, it was positively correlated with nitroglycerin-mediated diameter (NTD), blood pressure, and abdominal circumference. FFD was significantly higher in insulin-resistant subjects compared to noninsulin resistant (15.4 ± 7.5 vs. 10.5 ± 4.5). In insulin resistance group, Logistic regression analysis of all variables including cardiovascular risk factors and other variables has shown that FFD at a cutoff point more than 12.8% and HOMA–IR were the most specific predictors of CAD with a higher sensitivity (96.6% vs. 81.2%), a specificity (87.1% vs. 75.3%) and accuracy (92.4% vs. 83.1%) compared to FMD. while in noninsulin resistance group, FFD at a cutoff point 9.8% in addition to hypertension and smoking were the most specific predictors of CAD with a higher sensitivity (95.1% vs. 77.4%), a specificity (84.3% vs. 73%), and accuracy (90.3% vs. 75.1%) compared to FMD. Hence, in our study, FFD, compared to FMD, was a more accurate, more sensitive and more specific predictor of CAD all over the population of our study. Our study has shown that endothelial dysfunction measured by FFD provides an incremental value over insulin resistance in predicting the risk of CAD in nondiabetic individuals. However, individuals with combined insulin resistance and endothelial dysfunction were associated with a higher incidence of CAD than either one of them alone. Thus, we can identify a subset at a higher risk of CAD. This finding is relevant in clinical and research settings since insulin resistance, and noninvasive FFD can be readily available and have a potential to identify those subjects at a higher risk. In our study, FMD was one of the predictors of CAD but not a unique specific predictor of CAD compared to FFD as shown in the regression analysis. We are not in agreement with Inaba et al. studies in which FMD was a unique independent predictor of CAD.[18] FMD was negatively correlated with CAD and significantly lowered in patients with CAD compared to those without CAD (5.5 ± 3.1 vs. 8.5 ± 2.7). this was going with Gokce et al. study in which FMD was independently lowered in patients with CAD and cardiovascular events such as stroke, MI, or vascular death along the follow-up of the study compared to those without any evidence of CAD or cardiovascular event (4.4% ±2.8% vs. 7.0% ±4.9%).[19] In our study, the risk of CAD was significantly higher at FMD cutoff point <6.5% compared to higher levels. We are discordant to Gokce et al. study in which the risk of CAD was more higher (nine folds) at more higher FMD cutoff point 8.1% compared to our results, this may be due to different sample size (more than 900 individuals participate in Gokce et al. study while only 100 individuals participated in our study), racial difference (in Gokce et al. study, were mainly Hispanic while in our study are mainly white), different power and the variability among centers in both procedural technique and image analysis. Hyperinsulinemia was a predictor of CAD in our study as shown in a multivariate analysis of all variables including cardiovascular risk factors. It was positively correlated with CAD (P < 0.021) and increased incidence of CAD (P = 0.021) and this is going with many prospective studies like Després et al. who found that The greatest correlation of hyperinsulinemia with CAD has been present in Finland population with a very high frequency of CAD[20] and Yeni-Komshian et al. who also found that Several large population-based studies have shown that hyperinsulinemia is a surrogate marker for insulin resistance.[21]


  Conclusion Top


FFD is an independent predictor for CAD especially in insulin resistance subjects where they are more accurate and have more sensitivity and specificity than in noninsulin resistance subjects.

Recommendations

Further study is needed to verify the combined use of insulin resistance and noninvasive FFD testing for prediction of CAD in nondiabetics. New research is also warranted to validate other measures of endothelial function in a clinically useful way since FFD assessment was first done in our study and not standardized across institutions. With increasing experience and advances in technology, the measurement of brachial artery FFD will likely become the clinical technique of choice for the evaluation of endothelial function in the future.

Limitations of the study

Our study was limited by many factors including the variability among centers in procedural technique, image analysis and cutoff point of FFD for prediction of CAD.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Després JP, Lamarche B, Mauriège P, Cantin B, Dagenais GR, Moorjani S, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996;334:952-7.  Back to cited text no. 20
    
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