Influence of age and normal plasma fibrinogen levels on flow-mediated dilation in healthy adults

Influence of Age and Normal Plasma Fibrinogen Levels on Flow-Mediated Dilation in Healthy Adults Jason D. Allen,

MSC,

Joanie B. Wilson, BS, Richard T. Tulley, and Michael A. Welsch, PhD

E

levated plasma fibrinogen1 is associated with increased risk for atherosclerotic disease, acute myocardial infarction, and stroke.1– 6 Additionally, fibrinogen increases with age and may amplify the effects of other established cardiovascular risk factors.5 The detrimental effect of plasma fibrinogen and its intermediates is not fully clear, but is believed to involve coagulation of platelets, leukocytes, free fatty acids, and formation of thrombi.7 Recently, plasma fibrinogen has been proposed to act directly on the endothelial wall,4 causing a reduced ability to release endothelial-derived relaxing factors and decrease vasoactivity. Impaired endothelium-dependent vasodilation has been shown to be an early event in atherogenesis, preceding the formation of plaque8 and occlusive vascular disease in both primate models9 and humans.10 Consequently, high plasma fibrinogen contributes to a patient’s acute risk of cardiovascular disease through dysregulation of the coagulation process, and to longitudinal risk secondary to vascular dysfunction. Given fibrinogen’s role in vascular dysfunction, we hypothesized an inverse relation between plasma fibrinogen and brachial artery flow-mediated dilation (BAFMD) in asymptomatic patients. Accordingly, this study (1) examined the relation of plasma fibrinogen and age, and (2) evaluated the role of plasma fibrinogen on BAFMD using high-resolution ultrasonography. •••

Thirty nonsmoking volunteers (41 ⫾ 12 years, range 22 to 57) without overt signs of disease and normal plasma fibrinogen (283 ⫾ 43 mg/dl, range 174 to 341) were recruited. Subjects with acute medical conditions or active infection, on pharmacotherapy with known vascular effects (e.g., anti-inflammatory or cardiovascular medications), or those with Raynaud’s phenomenon, previous arm surgery, known history of cardiovascular or kidney disease, or diabetes were excluded. After explanation of the study, its benefits and risks, subjects signed an informed consent approved by the Pennington Biomedical Research Center Institutional Review Board. Brachial artery assessments were obtained using high-resolution ultrasound (Toshiba Powervision SSA-380A with a 7.5-MHz linear array transducer, New York, New York) before, during, and after 5 From the Department of Kinesiology and Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana. This study was supported in part by a grant from the National Dairy Council, Rosemont, Illinois. Dr Welsch’s address is: Department of Kinesiology, 112 H. P. Long Field House, Louisiana State University, Baton Rouge, Louisiana 70803. E-mail: [email protected]. Manuscript received February 4, 2000; revised manuscript received and accepted March 31, 2000. ©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 86 September 15, 2000

PhD,

Michael Lefevre,

PhD,

minutes of forearm occlusion. Before the study, subjects were instructed to fast and refrain from exercise for 12 hours and alcohol for 48 hours. Baseline ultrasound images were obtained after 15 minutes of supine rest. Ultrasound images were obtained in the longitudinal view, approximately 4 cm proximal to the olecranon process, in the anterior and/or medial plane. With the image depth initially at 4 cm, gain settings were adjusted to provide an optimal view of the anterior and posterior walls of the artery. Once settings were optimized, they were kept constant throughout the experiment. All imaging was performed on the nondominant arm with the subject in the supine position and forearm extended and slightly supinated. Forearm occlusion consisted of inflation of a blood pressure cuff, positioned approximately 1 cm distal to the olecranon process, to 240 mm Hg for 5 minutes. Brachial artery images were recorded on superVHS videotape for 30 seconds at baseline, and continuously from the final 30 seconds of occlusion until 5 minutes after release. Immediately following the vessel imaging, blood was drawn. Digital still images captured during diastole, as defined by the onset of the QRS complex, were subsequently analyzed using specialized imaging software (Media Cybernetics, Image-Pro Plus, Silver Spring, Maryland). Arterial diameters (millimeters) were calculated as the mean distance between the anterior and posterior wall at the vesselblood interface. Reproducibility of this technique in our laboratory yielded average mean difference in brachial artery diameter change for days, testers, and readers of 1.91%, 1.40%, and 0.21 mm, respectively, with intraclass correlation coefficients of 0.92, 0.94, and 0.90, respectively. Statistical analysis was performed using SPSS for Windows (version 9.0, SPSS Inc., Chicago, Illinois). Group values are expressed as mean ⫾ SD. Pearson’s product moment correlation was used to examine relations between brachial artery diameter percent change (BADPC) and age and between BADPC and plasma fibrinogen. An independent sample t test was used for comparisons between participants separated by age (younger patients ⬍50 years old and older patients ⱖ50 years old) for plasma fibrinogen levels and BADPC. Finally, stepwise multiple regression with BADPC as the dependent variable and plasma fibrinogen, age, total cholesterol, and blood pressure as the independent variables was performed. The ␣ level of p ⬍0.05 was required for statistical significance. Subjects’ data at baseline are shown in Table 1. Plasma fibrinogen was all within the normal range. Brachial artery diameter increased from 3.60 ⫾ 0.71 0002-9149/00/$–see front matter PII S0002-9149(00)01060-2

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TABLE 1 Baseline Participant Characteristics Mean

SD

Range

Minimum

Maximum

Age (yrs) Height (cm) Weight (kg) Heart rate (beats/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Total cholesterol (mg/dl) Low-density lipoprotein (mg/dl) High-density lipoprotein (mg/dl) Triglycerides (mg/dl) Plasma fibrinogen (mg/dl) Baseline artery diameter (mm)

42 170 76 63 120 76 195 114 56 116 283 3.60

12 8 15 11 13 8 39 34 15 59 43 0.71

35 28 55 50 54 32 171 141 64 275 167 2.62

22 157 48 34 104 64 113 48 27 33 174 2.55

57 185 103 84 158 96 284 189 91 308 341 5.17

Low-density lipoprotein (mg/dl) High-density lipoprotein (mg/dl) Triglycerides (mg/dl)

112 ⫾ 37 54 ⫾ 14 112 ⫾ 62

⫺0.46 ⫺0.82 ⫺0.55

0.65 0.42 0.59

0.002), but not for blood lipid or hemodynamic variables (Table 2). Stepwise multiple regression analysis, including plasma fibrinogen, age, total cholesterol, and blood pressure revealed plasma fibrinogen as the predominant predictor for BADPC with 31% of the model variance accounted for by the equation BADPC ⫽ 22.61 ⫺ (0.05836*PF), with no other variables entered into the model. •••

The unique finding of this study is the inverse relation between normal plasma fibrinogen levels and BAFMD. This finding indicates elevated plasma fibrinogen may decrease arterial responsiveness to certain vasodilatory signals, such as shear stress. Given the link between impaired flow-mediated dilation and cardiovascular disease,1,5,6,11,12 this suggests an additional important role for fibrinogen in maintaining chronic vascular integrity and/or function. In fact, multivariate analysis revealed plasma fibrinogen to be the predominant predictor for BADPC when age, total cholesterol, and blood pressure were included in the model. The mechanisms of action of fibrinogen on vasoreactivity are not fully understood but may involve alterations in blood viscosity and/or chemistry, causing ensuing chronic elevated stress on the artery FIGURE 1. Relation between BADPC and plasma fibrinogen. wall with gradual depletion of endothelial-derived relaxing factors. This may subsequently contribute to a loss in vasoactivity and render the TABLE 2 Independent t -Test Comparisons Between Younger and Older Groups vessel vulnerable to prothrombic facYounger Older tors, and ultimately proliferation of (n ⫽ 20) (n ⫽ 10) t p Value vascular smooth muscle and possibly Brachial artery diameter cardiovascular disease. The fact that Change (%) 7.65 ⫾ 3.97 2.90 ⫾ 3.93 3.08 0.005* plasma fibrinogen is modifiable by Age (yrs) 36 ⫾ 11 53 ⫾ 3 ⫺6.49 ⬍0.001* exercise,2,13,14 diet,15,16 and drug Plasma fibrinogen (mg/dl) 269 ⫾ 45 311 ⫾ 23 ⫺3.33 0.002* Peak blood flow velocity (cm/s) 178 ⫾ 36 169 ⫾ 55 0.533 0.59 treatment warrants further study to Heart rate (beat/min) 61 ⫾ 11 66 ⫾ 12 ⫺0.98 0.336 determine if a decrease in plasma Systolic blood pressure (mm Hg) 117 ⫾ 11 127 ⫾ 15 ⫺1.98 0.57 fibrinogen results in improved vascuDiastolic blood pressure (mm Hg) 76 ⫾ 6 76 ⫾ 10 0.67 0.95 lar function. Total cholesterol (mg/dl) 189 ⫾ 42 208 ⫾ 33 ⫺1.28 0.21 118 ⫾ 25 59 ⫾ 7 125 ⫾ 52

*p ⱕ0.05 between groups.

mm at baseline to 3.82 ⫾ 0.74 mm at peak dilation (within 90 seconds of cuff release), representing a 6.08% increase (range ⫺3.58% to 17.48%). Correlation analysis indicated significant inverse relations for BADPC and age (r ⫽ ⫺0.417, p ⫽ 0.02), and for BADPC and plasma fibrinogen (r ⫽ ⫺0.56, p ⫽ 0.001) (Figure 1). Comparison between the younger and older groups showed significant differences in BADPC (younger 7.65 ⫾ 3.97% and older 2.93 ⫾ 3.93%, p ⫽ 0.005) and plasma fibrinogen (younger 269 ⫾ 45 mg/dl and older 311 ⫾ 23 mg/dl, p ⫽ 704 THE AMERICAN JOURNAL OF CARDIOLOGY姞

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In summary, this study shows an inverse association between agerelated normal plasma fibrinogen levels and brachial artery flow-mediated dilation in 30 healthy nonsmokers. Given the links between impaired flow-mediated dilation and cardiovascular disease, this indicates an important role for fibrinogen in maintaining chronic vascular integrity and/or function, in addition to the risk for thrombus formation.

1. Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and the risk

of cardiovascular disease; the Framingham study. JAMA 1987;258:1183–1186. 2. Elwood PC, Yarnell JWG, Pickering J, Fehily AM, O’Brien JR. Exercise,

fibrinogen, and other risk factors for ischaemic heart disease (Caerphilly prospective heart disease study). Br Heart J 1993;69:183–187.

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3. Hamsten A. Hemostatic function and coronary artery disease. N Engl J Med 1995;332:677– 678. 4. Loscalzo J. The relation between atherosclerosis and thrombosis. Circulation 1995;86:III95–99. 5. Fowkes FGR, Lee AJ, Lowe GDO, Riemersma RA, Housley E. Inter-relationships of plasma fibrinogen, low density lipoprotein cholesterol, cigarette smoking and the prevalence of cardiovascular disease. J Cardiovasc Risk 1996;3:307–312. 6. Ma J, Hennekens CH, Ridker PM, Stampfer MJ. A prospective study of fibrinogen and risk of myocardial infarction in the Physicians Health Study. J Am Coll Cardiol 1999;33:1347–1352. 7. Ross R. The pathogenesis of atherosclerosis—an update. N Engl J Med 1986;314:488 –500. 8. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DS, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340: 1111–1115. 9. Fagiotto A, Ross R, Harker L. Studies of hypercholesterolemia in the nonhuman primate, I: changes that lead to fatty streak formation. Arteriosclerosis 1984;4:323–340.

10. Fish RD, Nabel EG, Selwyn AP, Ludmer P. Responses of coronary arteries of cardiac transplant patients to acetylcholine. J Clin Invest 1988;81:21–31. 11. Ernst E, Koenig W. Fibrinogen and cardiovascular risk. Vasc Med 1997;2: 115–125. 12. Kannel WB. Contributions of the Framingham study to the conquest of coronary artery disease. Am J Cardiol 1988;62:1109 –1112. 13. Connelly JB, Cooper JA, Meade TW. Strenuous exercise, plasma fibrinogen, and factor VII activity. Br Heart J 1992;67:351–354. 14. Stratton JR, Chandler WL, Schwartz RS, Cerqueira MD, Levy WC, Khan SE, Larson VG, Cain KC, Beard JC, Abrass IB. Effects of physical conditioning on fibrinolytic variables and fibrinogen in young and old healthy adults. Circulation 1991;83:1692–1697. 15. Haglund O, Mehta JL, Saldeen T. Effects of fish oil on some parameters of fibrinolysis and lipoprotein(a) in healthy subjects. Am J Cardiol 1994;15:189 – 192. 16. Calles-Escandon J, Ballor D, Harvey-Berino J, Ades P, Tracy R, Sobel B. Amelioration of the inhibition of fibrinolysis in elderly, obese subjects by moderate energy intake restriction. Am J Clin Nutr 1996;64:7–11.

Practice Guidelines for Electron Beam Tomography: A Report of the Society of Atherosclerosis Imaging Harvey S. Hecht,

MD,

for the Society of Atherosclerosis Imaging*

he use of electron beam tomography (EBT) for the detection and quantitation of coronary atheroscleT rotic plaque burden has become increasingly disseminated and has been accompanied by a corresponding increase in the scientific literature validating its utility.1 However, there has not been a consensus document providing guidelines for its application. The newly formed Society of Atherosclerosis Imaging, with representation from the imaging and epidemiologic communities, has undertaken to provide such guidelines. Operating under the following charter: “To promote and coordinate an integrated approach to atherosclerosis detection and prevention emphasizing noninvasive imaging and risk factor modification,” the Society of Atherosclerosis Imaging has developed recommendations that reflect current usage supported by emerging data. At the same time, considerable leeway is afforded for physician use according to individual practice patterns. Pending publication of peer reviewed data supporting other imaging modalities, these guidelines are currently applicable only to EBT. The American College of Cardiology/American Heart Association classifications I, II, and III are used to summarize indications. Class I: Conditions for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective. 1. Initial diagnostic test in ambulatory adults ⱕ65 years of age with atypical chest symptoms, in the absence of established cardiovascular disease.2–7 2. Supplementary diagnostic test in adults ⱕ65 years From the Arizona Heart Institute, Phoenix, Arizona. Dr. Hecht’s address is: Arizona Heart Institute, 2632 North 20th Street, Phoenix, Arizona 85006. Manuscript received and accepted April 6, 2000. *See Appendix for the Board of Directors of the Society of Atherosclerosis Imaging. ©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 86 September 15, 2000

of age with indeterminate stress test results, in the absence of established cardiovascular disease.8 –11 3. Emergency room evaluation of men ⱕ50 and women ⱕ60 years of age with chest pain and normal or nondiagnostic electrocardiograms, in the absence of established cardiovascular disease.12–14 Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/or efficacy of a procedure. IIa: Weight of evidence/opinion is in favor of usefulness/efficacy. 1. Men 45 to 65 years of age, women 55 to 75 years of age in the absence of established cardiovascular disease; subtract 10 years if any of the following risk factors are present (thus deemed “Intermediate Risk”)15–19: family history of premature coronary artery disease (first-degree male relative ⬍55 years of age and female relative ⬍65 years of age); hypertension; smoking (current or within last year); elevated low-density lipoprotein or reduced high-density lipoprotein based on current National Cholesterol Education Program guidelines.20 2. Diabetic men 35 to 65 years of age and women 35 to 75 years of age without known cardiovascular disease.21–23 3. Assist physicians in decision-making regarding initiation or change of drug therapy for cholesterol abnormalities in patients without established cardiovascular disease. IIb: Usefulness/efficacy is less well established by evidence/opinion. 1. Monitoring progression and effects of treatment after interval of ⱖ1 years.24 –26 2. Evaluating the etiology of heart failure.27,28 3. Following patients after cardiac transplantation.29 0002-9149/00/$–see front matter PII S0002-9149(00)01061-4

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