Background: In those without symptoms of coronary artery disease (CAD), the incidence of
coronary events is still high. The aim of this study was to evaluate whether flow mediated
dilatation (FMD) is a useful tool in identifying those with CAD in who are under 45 years of age.
Methods and results: Seventy five men below 45 years of age, hospitalized in order to
perform elective coronary angiography, were enrolled into the study. Based on coronary angiography
findings, they were divided into two groups: study group (Group A, n = 55) with
obstructive coronary lesions and the control group (Group B, n = 20) without significant
lesions in coronary arteries. In all subjects atherosclerosis risk factors were analyzed. Endothelial
dysfunction was assessed in ultrasound via FMD. FMD was significantly lower in the
study group than in the control group (3.92 &#177; 1.1 vs 6.51 &#177; 1.1, p < 0.001). FMD, as well as
age, diabetes and positive family history, appeared to be statistically significant CAD risk
factors. AUROC for FMD was 0.957 (p < 0.001), meaning this model had an almost complete
ability to predict the presence of CAD. AUROC for CAD diagnosis on the basis of significant
clinical parameters was 0.992 (p < 0.001), also representing almost complete ability of this model
to identify asymptomatic subjects with CAD risk.
Conclusions: The evaluation of endothelial function by the use of FMD in the population of
men below 45 years of age with diabetes and positive family history can help in identifying
subjects at high risk of coronary artery disease. (Cardiol J 2010; 17, 3: 288-292

Kaźmierski, Maciej

Krzych, Łukasz J.

Michalewska-Włudarczyk, Aleksandra

Tendera, Michał

English

Via Medica Journals

ORIGINAL ARTICLECardiology Journal2010, Vol. 17, No. 3, pp. 288–292Copyright © 2010 Via MedicaISSN 1897–5593288 www.cardiologyjournal.orgAddress for correspondence:  Maciej Kaźmierski, MD, 3rd Department of Cardiology, Medical University of Silesia,Ziołowa 45/47, 40–635 Katowice, Poland, tel./fax: +48 32 252 39 30, e-mail: maciejkazmierski@poczta.onet.plReceived: 11.09.2009 Accepted: 29.12.2009Diagnostic value of flow mediated dilatationmeasurement for coronary artery lesions inmen under 45 years of ageMaciej Kaźmierski1, Aleksandra Michalewska-Włudarczyk1,Łukasz J. Krzych2, Michał Tendera113rd Department of Cardiology, Medical University of Silesia, Katowice, Poland21st Department of Cardiac Surgery, Medical University of Silesia, Katowice, PolandAbstractBackground: In those without symptoms of coronary artery disease (CAD), the incidence ofcoronary events is still high. The aim of this study was to evaluate whether flow mediateddilatation (FMD) is a useful tool in identifying those with CAD in who are under 45 years of age.Methods and results: Seventy five men below 45 years of age, hospitalized in order toperform elective coronary angiography, were enrolled into the study. Based on coronary angio-graphy findings, they were divided into two groups: study group (Group A, n = 55) withobstructive coronary lesions and the control group (Group B, n = 20) without significantlesions in coronary arteries. In all subjects atherosclerosis risk factors were analyzed. Endothe-lial dysfunction was assessed in ultrasound via FMD. FMD was significantly lower in thestudy group than in the control group (3.92 ± 1.1 vs 6.51 ± 1.1, p < 0.001). FMD, as well asage, diabetes and positive family history, appeared to be statistically significant CAD riskfactors. AUROC for FMD was 0.957 (p < 0.001), meaning this model had an almost completeability to predict the presence of CAD. AUROC for CAD diagnosis on the basis of significantclinical parameters was 0.992 (p < 0.001), also representing almost complete ability of this modelto identify asymptomatic subjects with CAD risk.Conclusions: The evaluation of endothelial function by the use of FMD in the population ofmen below 45 years of age with diabetes and positive family history can help in identifyingsubjects at high risk of coronary artery disease. (Cardiol J 2010; 17, 3: 288–292)Key words: endothelial dysfunction, coronary artery disease, flow mediateddilatationIntroductionAmong those without coronary artery disease(CAD) symptoms, the incidence of coronary eventsis still high. This concerns also the population withearly onset of CAD, when the symptoms occur be-fore 45 years of age. According to many epidemio-logical studies, about 40% of all serious coronaryevents occur in 20% of the population, in subjectswith three or more risk factors. This means thatalmost 60% of all serious coronary events occur inthe larger population, in which classical atheroscle-rosis risk factors are less frequent or less intense.Therefore, in this group risk stratification is re-289Maciej Kaźmierski et al., Diagnostic value of FMD measurement for CAD diagnosticswww.cardiologyjournal.orgquired to define the risk of a coronary event moreprecisely. It has been proved that the risk of a coro-nary event correlates strongly with the presenceof atherosclerotic lesions [1]. In many studies,a positive correlation between endothelial dysfunc-tion and atherosclerotic lesions formation has beenobserved [2–4].The aim of this study was to evaluate whetherflow mediated dilatation (FMD) can be useful indiagnosing CAD in the population below 45 yearsof age.MethodsSeventy five male patients below 45 years ofage with a positive stress test result, admitted toour department in order to perform elective coro-nary angiography, were enrolled into the study.Based on coronary angiography findings, they weredivided into two groups: the study group (Group A)with obstructive coronary lesions and the controlgroup (Group B) without lesions in coronary arteries.Angiographic criteria: patients with coronarylesions narrowing vessel lumen £ 10% of vesselcross-section were considered without lesions andincluded in the control group. Patients with coro-nary lesions narrowing vessel lumen ≥ 50% of ves-sel cross section were included in the study group.Patients with coronary lesions narrowing artery lu-men 10–50% of vessel cross-section were exclud-ed from the study.The following atherosclerosis risk factors wereanalyzed: hypertension, hypercholesterolemia,diabetes, smoking, overweight or obesity, familyhistory of CAD. For the purpose of this study, thefollowing definitions were used: hypertension —arterial blood pressure equal to or exceeding 140//90 mm Hg and/or use of anti-hypertensive thera-py; hypercholesterolemia — plasma cholesterolconcentration exceeding 200 mg/dL at the time ofthe study or any time in the past; diabetes — diag-nosis of diabetes during index hospitalization or theuse of anti-diabetic agents and/or diet; obesity —body mass index (BMI) exceeding 30 kg/m2; smok-er — smoking at least one cigarette/day for at leastsix months; positive family history — myocardial in-farction in parents or siblings before 55 years of age.The study was approved by the BioethicsCommittee of the Medical University of Silesia andall patients provided written informed consent.Study protocolAll patients used vascular agents, such as ni-trates, calcium blockers, beta-adrenolytics, ACE--inhibitors, and statins which were administeredroutinely, also before ultrasound examination andcoronary angiography.Ultrasound examination of FMD was per-formed after overnight fast in the morning (beforemorning medications — minimum 8–12 hours postevening medications), after 15 minutes rest in thehorizontal position, by means of SONOS 5000 ul-trasoud scanner (Hewlett Packard, USA) with thelinear transducer 11 MHz.The diameter of the right brachial artery wasmeasured 3–5 cm above the antecubital space in theM-mode, at baseline. The measurement was per-formed in the end-diastolic phase, marking thediameter between anterior and posterior artery wallin the zone between media and adventitia (‘m-line’).An average of three measurements was taken andfurther analyzed to calculate FMD. Subsequently,a pneumatic tourniquet was placed on the upper partof the right forearm and inflated for four minutes toa pressure of 200 mm Hg or 50 mm Hg above sys-temic arterial blood pressure. Sixty seconds aftercuff release, the diameter of the right brachial ar-tery was measured three times. FMD was calcu-lated as an increase of vascular diameter (in per-centage) from the difference between maximum andbaseline brachial artery diameter.After a 15 minute break, a nitroglycerine-me-diated dilatation test (NTG-MD test) was performedusing 0.4 mg of sublingual nitroglycerine (Nitromint0.4 mg/dose, Egis Pharmaceuticals, Hungary). Be-fore nitroglycerine administration, brachial arterydiameter was measured three times as the baseline,and five  minutes after nitroglycerine administration,it was measured another three times. NTG-MD wascalculated as an increase of vascular diameter (inpercentage) from the difference between maximumand baseline brachial artery diameter [5].Coronary angiography was performed with theJudkins method from the right femoral artery ac-cess. After 6 F sheath insertion, angiography of bothcoronary arteries was done using contrast agentVisipaque 320 (Amersham Health, USA), showingright coronary artery in at least two opposite pro-jections and left coronary artery in at least four dif-ferent projections. Coronary artery narrowingswere calculated digitally (QCA, Quantitative Coro-nary Angiography).Statistical analysisQualitative variables were shown as absolutevalues and percentage and quantitative variables asmean and standard deviation (for normal distribu-tion) and as median and interquartile range (for dis-290Cardiology Journal 2010, Vol. 17, No. 3www.cardiologyjournal.orgtribution different from normal). Type of distribu-tion was assessed using the Shapiro-Wilk test. Thedifferences between the groups were interpretedon the basis of Student’s t-test (for normal distri-bution) and Mann-Whitney U test (for distributiondifferent from normal), and for qualitative data onthe basis of c2 test or the exact Fisher test. Addi-tionally, in order to diminish the influence of con-founding variables, multivariate analysis was per-formed in the model of logistic forward stepwiseregression, where the dependent variable was an-giographically verified presence of coronary arterydisease, and the independent variables were age,BMI, the presence of coexisting diseases, LDL cho-lesterol and triglycerides concentrations, diabetes,positive family history and FMD value. The abilityof FMD measurement, and of all clinical parame-ters together, to diagnose coronary artery diseasewas verified on the basis of ROC curve analysis (theaccuracy of patients’  assignment to study/controlgroup in particular FMD cut-off points). For themodel adjustment assessment, the value of the areaunder the ROC (AUROC) was calculated as was itsstatistical significance. P value < 0.05 was consi-dered statistically significant.ResultsSeventy five males were enrolled into thestudy, 55 into the study group (Group A) and 20 intothe control group (Group B). Patients in Group Amore frequently had diabetes and were overweight,and had significantly higher triglyceride concentra-tion in comparison to the control group. The char-acteristics of the groups are presented in Table 1.Patients in the study group had a significantlylower FMD value compared to the control group(Table 2).The analysis of coronary artery disease deter-minants is shown in Table 3. In this multivariatemodel, only the influence of FMD (logOR = 0.94,95% CI 0.86–0.97), age (logOR = 0.3, 95% CI 0.04––0.71), diabetes (logOR = 0.92, 95% CI 0.81–0.98)and positive family history (logOR = 0.92, 95% CI0.82–0.98) appeared to be statistically significant.ROC curve for CAD diagnosis on the basis ofFMD is presented in Figure 1. Each 1% increase inFMD value diminished the likelihood of CAD diag-nosis almost nine times (logOR = 0.102, 95% CI0.024–0.262, p < 0.001). The value of the AUROCwas 0.957 (p < 0.001), which means there was analmost complete ability of this model to predict thepresence of CAD.ROC curve for CAD diagnosis on the basis ofclinical parameters in the model of logistic regressionis shown in Figure 2. After adjustment for statistical-ly significant determinants of CAD prevalence,Table 3. Determinants of coronary artery disease (CAD) prevalence in multivariate model.Variable logOR 95% CIFlow mediated dilatation (%) Step 1 0.94 0.859–0.974Age (years) Step 2 0.3 0.04–0.71Diabetes Step 3 0.922 0.807–0.979Positive family history of CAD Step 4 0.925 0.817–0.98R2 = 0.655; p < 0.001; logOR — logistic odds ration value; 95% CI — 95% confidence interval of logistic odds rationTable 2. Flow mediated dilatation (FMD) value.Variable Group A Group B pFMD (%) 3.92 ± 1.1 6.51 ± 1.1 < 0.001Table 1. Characteristics of the groups.Variables Group A Group B pAge (years) 38.1 ± 4.3 40.9 ± 4.8 0.006BMI [kg/m2] 27.7 ± 3.3 27.0 ± 1.9 0.5Overweight (%) 100.0 83.6 0.05Smoking (ever) (%) 85.4 100.0 0.07Diabetes (%) 25.0 7.3 0.05Arterial 50.9 70.0 0.1hypertension (%)Positive family 45.0 30.0 0.2history of CAD (%)Total cholesterol 224.6 ± 48.6 216.8 ± 33.7 0.5[mg/dL]LDL cholesterol 151.9 ± 43.5 139.8 ± 32.7 0.3[mg/dL]Triglycerides 167.8 ± 68.4 131.0 ± 53.5 0.02[mg/dL]BMI — body mass index; CAD — coronary artery disease291Maciej Kaźmierski et al., Diagnostic value of FMD measurement for CAD diagnosticswww.cardiologyjournal.orgAUROC was 0.992 (p < 0.001), which representsan almost complete ability of this model to identifysubjects at risk of CAD.DiscussionEndothelium is the largest endocrine gland inthe organism, which maintains circulatory systemhomeostasis using many biological transmitters [6].As a non-invasive ultrasound technique which en-ables the evaluation of the brachial artery, FMD hasbeen commonly recognized as a useful index ofendothelial function [5]. The methodology de-scribed for the first time by Celermajer et al. [7]is based on evoking brachial artery ischemia andevaluating subsequent artery dilatation due to post-ischemic flow increase. Artery dilatation dependson the increase of shear stress, caused by bloodpressure and blood flow velocity increase. Shearstress is defined as a force acting on the vascularwall area unit. As a response for the shear stress,endothelial nitric oxide is released and vascularsmooth muscles are relaxed [8, 9]. Decreased FMDrepresents endothelial dysfunction, and can be ob-served in subjects with coronary artery risk factorsand with symptomatic CAD [10–17].Kirma et al. [18] investigated the relationshipbetween FMD and CAD risk factors in 150 patientswith stable angina, evaluating the following risk fac-tors: age, diabetes, positive family history, smok-ing, hypertension, BMI and concentrations of totalcholesterol, HDL-cholesterol, LDL-cholesterol andtriglycerides. In univariate analysis, FMD correlat-ed negatively with age and BMI, and in patients withdiabetes significantly lower FMD was observed. Instepwise multivariate analysis, estimating whichrisk factors have significant influence on endothe-lial function, this relationship was confirmed withregard to diabetes and age, but not to BMI. No cor-relation was shown between FMD and hypercho-lesterolemia, positive family history, hypertensionor smoking [18].In our study, the analysis of CAD prevalencedeterminants confirmed the results of Kirma et al.[18] concerning the influence of age and diabeteson FMD value. However, it has to be underlined thattheir study group was significantly older (57.0 ±± 11.1 years) than ours. It has already been provedthat FMD decreases as age increases [19]. Therefore,our findings concerning the evaluation of FMD inthose below 45 years of age is even more significant.One of our findings was that positive familyhistory of early CAD onset has significant influ-ence on FMD variability as a CAD risk factor,which was not confirmed by Kirma et al. [18]. Ne-vertheless, there are strong indications that posi-tive family history is a significant risk factor ofcoronary artery disease, especially for young pa-tients. Relative risk of CAD in siblings of patientswith CAD is increased 2–12 times in comparisonto the general population [20].However, we are the first to report, on thebasis of ROC curve analysis for CAD, that low FMDvalue can (with high probability) identify subjectswith asymptomatic coronary artery disease.Figure 2. ROC curve for coronary artery disease dia-gnosis on the basis of flow mediated dilatation.Figure 3. ROC curve for coronary artery disease dia-gnosis on the basis of clinical parameters in the modelof logistic regression.292Cardiology Journal 2010, Vol. 17, No. 3www.cardiologyjournal.orgConclusionsThe evaluation of endothelial function by theuse of FMD in the population of men below 45 yearsof age with diabetes and a positive family historycan help in identifying subjects at high risk of coro-nary artery disease.AcknowledgementsThe authors do not report any conflict of inte-rest regarding this work.This study was supported by grant numberKNW-2-201/08 from Medical University of Silesia,Poland.References1. Multiple Risk Factors Intervention Trial Research Group. Mor-tality rates after 10.5 years for participants in the Multiple RiskFactors Intervention Trial: Findings related to a priori hypothe-sis of the trial. JAMA, 1990; 263: 1795–1801.2. Hasdai D, Gibbons RJ, Holmes DR Jr, Higano ST, Lerman A.Coronary endothelial dysfunction in humans is associated withmyocardial perfusion defects. Circulation, 1997; 96: 3390–3395.3. Zeiher AM, Krause T, Schachinger V, Minners J, Moser E.Impaired endothelium-dependent vasodilatation of coronaryresistance vessels is associated with exercise-induced ischemia.Circulation, 1995; 91: 2345–2352.4. Vane JR, Anggard EE, Botting RM. Regulatory functions of thevascular endothelium. N Engl J Med, 1990; 323: 27–36.5. Corretti MC, Anderson TJ, Benjamin EJ et al. Guidelines for theultrasound assessment of endothelial-dependent flow-mediatedvasodilatation of the brachial artery: A report of the InternationalBrachial Artery Reactivity Task Force. International Brachial Ar-tery Reactivity Task Force. J Am Coll Cardiol, 2002; 39: 257–265.6. Anggård EE. The endothelium — the body’s largest endocrinegland? J Endocrinol, 1990; 127: 371–375.7. Celermajer DS, Sorensen KE, Gooch VM et al. Non-invasivedetection of endothelial dysfunction in children and adults atrisk of atherosclerosis. Lancet, 1992; 340: 1111–1115.8. Joannides R, Haefeli WE, Linder L et al. Nitric oxide is responsi-ble for flow-dependent dilatation of human peripheral conduitarteries in vivo. Circulation, 1995; 91: 1314–1319.9. Lieberman EH, Gerhard MD, Uehata A et al. Flow-induced va-sodilatation of the human brachial artery is impaired in patients< 40 years of age with coronary artery disease. Am J Cardiol,1996; 78: 1210–1214.10. Celermajer DS, Sorensen KE, Bull C, Robinson J, Deanfield JE.Endothelium-dependent dilation in the systemic arteries ofasymptomatic subjects relates to coronary risk factors and theirinteraction. J Am Coll Cardiol, 1994; 24: 1468–1474.11. Mombouli JV, Vanhoutte PM. Endothelial dysfunction: Fromphysiology to therapy. J Mol Cell Cardiol, 1999; 31: 61–74.12. Corretti MC, Plotnick GD, Vogel RA. Correlation of cold pressorand flow-mediated brachial artery diameter responses with thepresence of coronary artery disease. Am J Cardiol, 1995; 75:783–787.13. Gaenzer H, Neumayr G, Marschang P, Sturm W, Kirchmair R,Patsch JR. Flow-mediated vasodilatation of the femoral and bra-chial artery induced by exercise in healthy nonsmoking andsmoking men. J Am Coll Cardiol, 2001; 38: 1313–1319.14. Kuvin JT, Patel AR, Sliney KA et al. Peripheral vascular endo-thelial function testing as a noninvasive indicator of coronaryartery disease. J Am Coll Cardiol, 2001; 38: 1843–1849.15. Kuvin JT, Patel AR, Sidhu M et al. Relation between high-densi-ty lipoprotein cholesterol and peripheral vasomotor function. AmJ Cardiol, 2003; 92: 275–279.16. Patel AR, Kuvin JT, Sliney KA et al. Gender-based differencesin brachial artery flow-mediated vasodilatation as an indicatorof significant coronary artery disease. Am J Cardiol, 96: 1223––1226.17. Neunteufl T, Katzenschlager R, Hassan A et al. Systemic endo-thelial dysfunction is related to the extent and severity of coro-nary artery disease. Atherosclerosis, 1997; 129: 111–118.18. Kirma C, Akcakoyun M, Esen AM et al. Relationship betweenendothelial function and coronary risk factors in patients withstable coronary artery disease. Circ J, 2007; 71: 698–702.19. Herrington DM, Fan L, Drum M et al. Brachial flow-mediatedvasodilator responses in population-based research: Methods,reproducibility and effects of age, gender and baseline diameter.J Cardiovasc Risk, 2001; 8: 319–328.20. Rissanen AM, Nikkilä EA. Coronary artery disease and its riskfactors in families of young men with angina pectoris and incontrols. Br Heart J, 1977; 39: 875–883.

Diagnostic value of flow mediated dilatation measurement for coronary artery lesions in men under 45 years of age

https://journals.viamedica.pl/cardiology_journal/article/download/21379/16983

Diagnostic value of flow mediated dilatation measurement for coronary artery lesions in men under 45 years of age

Abstract

Similar works

Full text

Available Versions

Via Medica Journals