Prerequisites and factors that influence the flow-mediated dilation.
Atherosclerosis, with its complications, is the most frequent cause of death all over the world, and it is the underlying cause of about 50% of all deaths in developed countries (1).
Recent studies showed the key role played by inflammation and immune responses in development, progression, and rupture of atherosclerotic plaque (2,3,4). The presence of an immune reaction and/or infective antigens as potential triggers of atherogenesis (5,6) makes atherosclerosis be considered as an autoimmune disease in which the adaptive immune system is targeted against self-antigens modified by biochemical factors such as oxidative stress and hypercholesterolemia (7). These give rise to plaque birth (8,9) and the inflammatory status of the plaque makes the lesions unstable, inducing their abruption and acute thrombotic obstruction. Therefore, it induces impairment in endothelial function in bioactive antiatherogenic or proatherogenic molecules production (10), although other factors could increase such an imbalance: age (11), sex (12), hypertension (13), obesity (14), smoking (15), dyslipidemia (16), diabetes (17), all able to increase oxidative stress and vascular inflammation (18), morphological wall alterations and subsequently progression of atheromatous lesions.
The initial atherosclerosis stages silently and symptom free occur since childhood (19); the clinical expressions (i.e., sudden cardiac death, myocardial infarction, angina pectoris, stroke, aortic aneurysm, renovascular hypertension, and intermittent claudication) involve 2 over 3 men and 1 over 2 women after age 40, and almost 60% of deaths are due to a cardiovascular disease cause (20). Thus, there has been an increase in recognition of the importance of subclinical atherosclerosis, and early detection of this insidious process must be the goal for improving cardiovascular health through prevention, and treatment of risk factors.
Currently, non-invasive risk profile assessments can be evaluated not only with some laboratory parameters, (lipids and systemic inflammation markers as white blood cells, reactive C protein and erythrocyte segmentation rate), but also with ultrasonographic methods that detect subclinical atherosclerosis. Three internationally validated methods had been adopted in order to evaluate endothelium function: brachial artery flow-mediated vasodilation (FMD) (21,22), antero-posterior abdominal aorta diameter (APAO) (23) and intima-media thickness of the common carotid artery (CCA-IMT) (24,25). Cause of their non-invasiveness, feasibility and cheap cost, these techniques are the best tools for the physicians to assess functional and morphological alterations of the arteries before a cardiovascular event occurs and the feasibility of therapies to reduce atherosclerosis burden (26).
2. FMD technique
The endothelium is a real “organ”, endowed with autocrine and paracrine properties and playing an essential role in controlling vasomotion by producing molecules able to modulate blood, such as nitric oxide (NO), the most important vasodilator molecule produced by endothelial cells) (27). Shear stress is the main element able to determine increasing in NO production, its action being exerted perpendicularly to the long axis of the vessel.
Nevertheless, endothelial cells can also produce substances with vasoconstrictor action, as endothelin-1, (27) above all in case of increased age, hyperhomocysteinemia, smoking, diabetes, hypercholesterolemia, and hypertension (28): in these case it could be detected the presence of reduced vasodilating response to endothelial stimuli. Instead, diet and exercise can improve endothelial function (29). Lipid-lowering therapy (30,31), antioxidants (32), estrogen replacement (33) and treatment with angiotensin-converting enzyme inhibition or receptor blockade (34) improve this response.
Thus, endothelial dysfunction is considered the basic pathogenic mechanism of cardiovascular disease (35) and therefore can be considered as an early marker of cardiovascular risk.
In fact, the endothelial dysfunction seems to be the earliest event in the process of atherosclerotic plaque formation, appearing even before structural lesion of the vessel wall (36); for this reason the evaluation of endothelial function could be a useful tool for early stratification of patients at risk for cardiovascular events.
Studies in postmenopausal women suggest that endothelial dysfunction may be a predisposing factor for the development of hypertension (37) and diabetes (38), thus being not only a consequence of risk factors but also a pathogenetic mechanism for their onset.
Moreover, impaired endothelium-dependent vasomotion may contribute to the genesis of cardiovascular events by modulating the stability of plaque and coronary vasospasm. In fact, the analysis of Lerman and Zeiher (39) showed that endothelial dysfunction, assessed both at coronary and peripheral level, is significantly predictive of cardiovascular events independently of the presence of traditional cardiovascular risk factors.
3. Procedure description
A non-invasive method to assess endothelium-dependent flow-mediated vasodilation (FMD) was developed in the 1990s: it consisted in inducing endothelial cells to release NO (40,41) through mechanical stimulation originating from increasing in vessel wall “shear stress”. It is usually performed at brachial artery level by high-frequency ultrasonographic imaging (21).
It is performed in a quiet, temperature-controlled (22–24 C) room, early in the morning and it adopts a high resolution ultrasonograph connected to an image analysis system and a sphygmomanometer cuff applied around the forearm to create a flow stimulus in the brachial artery. The examination requires the patients to be supine, at rest, fast for at least 8 to 12 hours before the study; all vasoactive medications (calcium channel blockers, ß-adrenergic blocking agents, nitrates and converting enzyme inhibitors) should be withheld for at least 4 half-lives, if possible. Moreover, subjects should avoid substances that might impair FMD such as caffeine, high-fat foods, and vitamin C or use tobacco for at least 4 to 6 hours before the study (table 1).
|Hours||The examination should be performed at the same time of day|
|Temperature||Ultrasonographic evaluation should be performed at constant temperature, in an environment equipped with air conditioning|
|Drugs||All vasoactive drugs should be discontinued the night before the exam|
|Coffee and The||The day of the examination, the patient should refrain from taking coffee or tea|
|Smoking||Patients should abstain from smoking|
|Influence of food||Patients should not take copious meals or high in fat|
|Brachial artery diameter||It must be between 2.5 and 5 mm|
The 7,5 MHz electronic probe is positioned 4–5 cm above ante-cubital fossa to obtain longitudinal B-mode vascular scanning of the brachial artery with clear anterior and posterior intimal-lumen interfaces, and once the optimal artery image is achieved, the probe can be maintained in the right position using a mechanical arm. A pulsed wave Doppler recording is obtained from the midartery.
The procedure lasts 9 minutes: the first minute evaluate baseline diameter, measured at the onset of the R-wave on the electrocardiogram.
At the end of the first minute, the cuff is inflated 200-250 mmHg in order to close arterial inflow of the forearm (42). This causes ischemia and, consequentially, dilation of downstream resistance vessels by autoregulatory mechanisms.
After the sixth minute, the cuff is rapidly deflated: a brief high-flow state through the brachial artery to accommodate the dilated resistance vessels happens, and this reactive hyperemia produces a shear stress stimulus that induces the endothelium to release nitric oxide with subsequent vasodilation of the brachial artery between the 6th and 9th minute.
The software calculates FMD value as percentage of increasing of diameter value from baseline:
FMD = [(postiperemia diameter - baseline diameter) / baseline diameter] x 100
The maximal increase in diameter occurs approximately 60 to 90 seconds after cuff release. FMD values greater than 5-10% are considered “normal” (21). A schematic overview of this imaging technique could be observed in figure 1a.
This reactive hyperemia phase is confirmed by measuring the arterial blood flow using pulse-wave Doppler. The peak blood flow in the brachial artery is obtained with the sample volume in the centre of the artery and a correction angle of 70 . It is estimated at rest and during the first 15 s after cuff deflation, taking the average of the pulsed Doppler velocity signal of 3 measurements. The maximum speeds considered normal is 50–70 cm/s. Reactive hyperemia is calculated as the ratio of the maximal velocity divided by the maximal velocity at baseline.
Because of its low reproducibility and accuracy (43,44), the technique requires very high methodology accuracy and a mechanical support for the probe with micrometer adjustment to prevent movement of the vascular probe, and specific software ("FMD Studio") to measure second to second changes in artery caliber (21). The variations in caliber measured are small (from 0 to 15%), so the FMD represents a stimulus-type “on / off” poorly modulated.
Therefore, in order to obtain results that have a clinical validity, it is necessary to study a large number of patients. In support of the role of endothelial function as marker of cardiovascular risk and of the validity of the FMD method, there is also correlation with the invasive test data of coronary endothelial function (45) and with the severity and extent of atherosclerosis coronary (46).
Moreover, the noninvasive nature of the technique allows repeated measurements over time to study the effectiveness of various interventions that may affect vascular health.
Up to now the infrarenal anteroposterior diameter of abdominal aorta (APAO) has been always related to the abdominal aortic aneurysms (AAAs), as a measurement to be used in the diagnostic and follow-up phase of this disease and for surgical intervention planning.
An abdominal aortic aneurysm is defined by some authors as an infrarenal aortic diameter ≥ 3.0 cm, or a ratio between infrarenal and suprarenal aorta diameters greater than 1.2, all measured by ultrasound B-mode (47). As coronary heart disease and stroke continue to be the leading causes of death and disability among adults in developed countries, an early detection of vascular damage and, consequently, adequate cardiovascular risk stratification has received an intense attention in the last years in order to decrease the impact of cardiovascular disease.
To detect the “primum movens” of atherosclerotic disease, several studies have been conducted in the last years for identify new ultrasonographic markers (48).
Intima-media thickness of abdominal aorta has been firstly suggested as cardiovascular risk marker in patients stratification risk profile (49).
Recently, in addition to arterial wall thickening, attention has been paid on APAO as a possible early marker of atherosclerosis (before clinical manifestations have become evident). Indeed, arterial dilatation is a well-known age-related manifestation, and some of the molecular events causing this alterations are involved in the pathogenesis of cardiovascular disease (50,51).
There is a relationship between APAO in the non-aneurysmal range (<30 mm in diameter) and all-cause mortality: in a cohort of 12203 men aged 65 years and older infrarenal aortic diameter is turned out to be an independent predictor of all-cause mortality, particularly cardiovascular mortality (52). In another study on 4734 participants > 65 years old underwent to abdominal aortic ultrasound evaluation, has been demonstrated that for those with an infrarenal aortic diameters >2.0 cm, there was a significantly higher risk of future cardiovascular events and total mortality, suggesting a value of infrarenal aortic diameters between 2.0 and 3.0 cm as another manifestation of subclinical atherosclerosis (53).
Furtheremore, Allison et al (54) showed that age, gender, body mass index, and the presence and extent of calcified atherosclerosis in both the abdominal aorta and iliac arteries are significantly associated with increasing aortic diameter independently of other cardiovascular risk factors. A study by Ciccone et al. involving women with polycystic ovary syndrome PCOS (55) showed that the increase in APAO is the earliest arterial alteration in women with PCOS, thus preceding the IMT of other arteries such as common carotid arteries and common femoral arteries. This identifies APAO as an early marker of atherosclerosis.
However, this alteration seems to be due to body weight secondary to PCOS and not to PCOS
To explain these findings it can be hypothesized that APAO may represent a measure of cumulative exposure to genetic and environmental risk factors implicated in atherosclerosis development. For these reasons, APAO can be considered as an early marker of cardiovascular risk, and because of its noninvasive measurement and feasibility might be used to investigate determinants of atherosclerosis at an early stage of the process and to assess modifiers of atherosclerosis disease progression, such as lifestyle and pharmacological interventions.
5. Procedure description
Wilmink and colleagues (57,58) showed that the use of ultrasounds to measure the infrarenal aortic diameter is attractive as it is rapid, cheap, and noninvasive. The good accuracy of infrarenal aortic diameter measurements by ultrasound makes this method acceptable for clinical decision-making.
With the patient in supine position, the examination is carried out with a 3.5 MHz electronic probe placed one centimetre left of the umbilicus. The longitudinal ultrasound scans allow the study of the aorta and the best image in long axis projection of the abdominal aorta is used for the measurement. To improve the image acquisition, subjects are asked to keep fasting for at least 6-8 hours and follow a fiber diet for the two days prior to the examination to reduce intestinal bloating (diet preparation). To reduce the bias and interobserver variability the study of infrarenal abdominal aorta should be performed by same physician (59,60).
In the study of Ciccone et al.(55) the anteroposterior diameter of the aorta was defined as the maximal external cross-sectional measurement. It was calculated as the distance between the near and the far walls of the abdominal aorta on images that were frozen in systole. All the measurements were performed at 0.5, 1, and 2 cm above the umbilicus and were expressed in centimetres (see also Figure 1c and 1d).
However, in several studies the position of the probe and the part of abdominal aorta evaluated may be different.
van den Bosch et al. (61) studied distal aortic diameter to assess the relationship between abdominal aortic diameter and peripheral arterial occlusive disease. They demonstrated that both patients with an aortic diameter too large and patients with an aortic diameter too small are prone to peripheral arterial occlusive disease.
The study of Norman P. et al. (52) was carried out using a 3.75 mol/L Hz probe to measure the maximum transverse and antero-posterior diameter of the infrarenal aorta. The largest measurement was recorded as the aortic diameter.
Pleumeekers et al. (62) evaluated the observer variability of ultrasound measurements of proximal and distal part of the abdominal aorta. Their results were that ultrasound measurements are more accurate for the distal than for the proximal aorta measurement and the definition of the aortic diameter based on a combination of both distal and proximal measurement may be more accurate.
Atherosclerosis is a disease with a slowly progressive course and a long asymptomatic period. The clinical manifestations generally appear in middle age (63), and the first event triggered by atherosclerosis can be fatal.
Since the atherosclerotic disease is a multidistrict and multifocal process, identifying the changes of the vascular wall at subclinical stages of atherosclerosis is essential in assessing global cardiovascular risk (64) and in promoting the use of preventive strategies, as well as optimization of preventive and protective care.
Among imaging techniques for detection of early preclinical stages of atherosclerosis, the best is the measurement of the carotid intima-media thickness (CCA-IMT) using ultrasound high-resolution B-mode; the evaluation of this parameter is a noninvasive and reproducible method for identifying and quantifying subclinical vascular disease.
Many studies demonstrated the role of CCA-IMT in the early evaluation of atherosclerosis disease. In fact, this parameter was found to be associated with the presence of cardiovascular risk factors (67,68,69) and with atherosclerotic lesions in other vascular districts, such as coronary and lower extremity arteries (70,71,72). Gasparyan (73) already put on evidence the importance of carotid ultrasound assessment in the clinical practice. Apart from CCA-IMT evaluation, the ultrasound evaluation should consider all the characteristics of carotid wall: it is necessary to evaluate IMT and, at the same time, morphological aspects of carotid wall.
Prospective epidemiological studies showed that individuals with elevated carotid IMT are more likely to suffer from cardiovascular or cerebrovascular events, suggesting that thickened carotid IMT is a powerful and independent indicator of the likelihood of general arteriosclerosis (74,75). The predictive power of carotid IMT is maintained even after adjustment for major cardiovascular risk factors. Thus, measurement of IMT may provide informations in addition to traditional risk factors during assessment of global cardiovascular risk profile in asymptomatic subjects (76).
Moreover, changes in carotid IMT may be used as a measure of efficacy of pharmacologic intervention.
7. Procedure description
Carotid ultrasound can be performed using vascular echographic apparatus equipped with high-frequency transducers (usually 3-10 MHz and linear array) and appropriate software. The patient should be positioned supine with slight (45 ) hyperextension and rotation of the neck in the direction opposite the probe.
CCA-IMT is defined as the distance between the lumen-intima interface and the media-adventitia interface, which corresponds to the inner and outer echogenic lines seen on the B-mode ultrasound image [see figure 1b] (24,79).
Measurement of carotid IMT (c-IMT) is traditionally performed with the image of the carotid artery in the longitudinal axis, revealing the common carotid artery, the carotid bifurcation, and the internal and external carotid arteries.
Although these measurements have been performed for years, significant variability exists when measuring the near wall due to technical and acoustic difficulties encountered when imaging the c-IMT of the near wall (80). Due to these technical limitations, clinical measurement of c-IMT using B-mode ultrasound is often applied to the far (posterior) wall of the common carotid artery.
IMT is measured at about 2 cm proximal to the dilation of the bulb of the common carotid artery.
Three measurements coming from three different sites [according to the method described by Pignoli et al. (79): about 2 cm above the flow-divider, about ½ cm above the flow-divider and in middle zone] are considered for IMT evaluation. An average of all these values would be calculated at the end of the measures.
Mean IMT (m-IMT) and maximum IMT (M-IMT) are measured. m-IMT represents the mean value of all measurements at each common carotid artery, averaging the left and right sides. M-IMT represents the mean value of the single highest IMT measurements at each common carotid artery, averaging the left and right sides. Carotid plaque is defined as the presence of a greater than 1.5 mm c-IMT measurement or an area within the carotid artery that is at least 50% greater than the size of the surrounding vessel wall.
The same physician should perform the evaluation in order to reduce bias and improve the results.
A problem associated with the ultrasonographic IMT measurement is the variation in the readings, which leads to different results of repeated measurements from the same observer. In general, the inter- and intra-observer errors are acceptable and the technique has a good reproducibility (81,82).
Lusis A. J. 2000Atherosclerosis. 2000; 407 233 41.
Ross R. 1999 Atherosclerosis: an inflammatory disease.1999; 340 115 126.
Jan M. Meng S. Chen N. C. Mai J. Wang H. Yang X. F. 2010 Inflammatory and autoimmune reactions in atherosclerosis and vaccine design informatics. . 2010;2010:459798. Epub 2010 Apr 15.
Libby P. Okamoto Y. Rocha V. Z. Folco E. 2010 Inflammation in atherosclerosis: transition from theory to practice. . 2010; 74 2 213 220.
Guan X. R. Jiang L. X. Ma X. H. Wang L. F. Quan H. Li H. Y. 2010 Respiratory syncytial virus infection and risk of acute myocardial infarction. 2010; 340 5 356 9.
Makris G. C. Makris M. C. Wilmot V. V. Geroulakos G. Falagas M. E. 2010 The role of infection in carotid plaque pathogenesis and stability: the clinical evidence.2010; 8 6 861 72. Review.
Nilsson J. Hansson G. K. 2008Autoimmunity in atherosclerosis: a protective response losing control? 2008; 263 5 464 478.
Nilsson J. Wigren M. Shah P. K. 2009 Regulatory T cells and the control of modified lipoprotein autoimmunity-driven atherosclerosis. . 2009; 19 8 272 276.
Hansson G. K. 2005 Mechanisms of disease: inflammation, atherosclerosis, and coronary artery disease. . 2005; 352 16 1685 1626.
Vanhoutte P. M. Shimokawa H. Tang E. H. Feletou M. 2009 Endothelial dysfunction and vascular disease.2009; 196 2 193 222.
Juonala M. Magnussen C. G. Venn A. Dwyer T. Burns T. L. Davis P. H. Chen W. Srinivasan S. R. Daniels S. R. Khnen M. Laitinen T. Taittonen L. Berenson G. S. Viikari J. S. Raitakari O. T. 2010 Influence of Age on Associations Between Childhood Risk Factors and Carotid Intima-Media Thickness in Adulthood: The Cardiovascular Risk in Young Finns Study, the Childhood Determinants of Adult Health Study, the Bogalusa Heart Study, and the Muscatine Study for the International Childhood Cardiovascular Cohort (i3C) Consortium. . 2010; 122 24 2514 20.
Vaccarino V. Badimon L. Corti R. de Wit C. Dorobantu M. Hall A. Koller A. Marzilli M. Pries A. Bugiardini R. 2010 Ischemic Heart Disease in Women: Are There Sex Differences in Pathophysiology and Risk Factors?: Position Paper from the Working Group on Coronary Pathophysiology & Microcirculation of the European Society of Cardiology. Cardiovasc Res. 2010 Dec 14. [Epub ahead of print]
Dzau V. J. 1990 Atherosclerosis and hypertension: mechanisms and interrelationships.. 1990;15(supplement 5): S59 S64.
Mangge H. Almer G. Truschnig-Wilders M. Schmidt A. Gasser R. Fuchs D. 2010 Inflammation, adiponectin, obesity and cardiovascular risk.. 2010; 17 36 4511 20.
Lloyd-Jones D. M. Wilson P. W. F. Larson M. G. Beiser A. Leip E. P. D’Agostino R. B. Levy D. 2004 Framingham risk score and prediction of lifetime risk for coronary heart disease.. 2004; 94 1 20 24. doi: 10.1016/j.amjcard.2004.03.023.
Ishigaki Y. Oka Y. Katagiri H. 2009 Circulating oxidized LDL: a biomarker and a pathogenic factor. 2009; 20 5 363 9.
Almdal T. Scharling H. Jensen J. S. Vestergaard H. 2004 The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up.2004; 164 13 1422 6
Deanfield J. E. Halcox J. P. Rabelink T. J. 2007Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007; 115 10 1285 1295.
Toth P. P. 2008 Subclinical atherosclerosis: what it is, what it means and what we can do about it. 2008, 62:1246-1254.
Rosamond W. Flegal K. Furie K. Go A. Greenlund K. Haase N. Hailpern S. M. Ho M. Howard V. Kissela B. Kittner S. Lloyd-Jones D. McDermott M. Meigs J. Moy C. Nichol G. O’Donnell C. Roger V. Sorlie P. Steinberger J. Thom T. Wilson M. Hong Y. American Heart Association Statistics Committee and Stroke Statistics Subcommittee 2008 Heart Disease and Stroke Statistics--2008 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. 2008, 117: e25 e146.
Corretti M. C. Anderson T. J. Benjamin E. J. et al. 2002Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002; 39 257 65.
Tomiyama H. Yamashina A. 2010 Non-invasive vascular function tests: their pathophysiological background and clinical application. 2010; 74 1 24 33.
Leite C. C. Wajchenberg B. L. Radominski R. Matsuda D. Cerri G. G. Halpern A. 2002 Intra-abdominal thickness by ultrasonography to predict risk factors for cardiovascular disease and its correlation with anthropometric measurements. . 2002 Aug; 51 8 1034 40.
Touboul P. J. Hennerici M. G. Meairs S. Adams H. Amarenco P. Bornstein N. Csiba L. Desvarieux M. Ebrahim S. Fatar M. Hernandez Hernandez R. Jaff M. Kownator S. Prati P. Rundek T. Sitzer M. Schminke U. Tardif J. C. Taylor A. Vicaut E. Woo K. S. Zannad F. Zureik M. 2007Mannheim Carotid Intima-Media Thickness Consensus (2004-2006). 2007; 23 1 75 80.
Ciccone M. M. Balbarini A. Porcelli M. T. Santoro D. Cortese F. Scicchitano P. Favale S. Butitta F. De Pergola G. Gullace G. Novo S. 2010Carotid artery intima-media thickness: normal and percentile values in the italian population (CAMP study). 2010 [in press].
Ciccone M. M. Favale S. Scicchitano P. Mangini F. Mitacchione G. Gadaleta F. Longo D. Iacoviello M. Forleo C. Quistelli G. Taddei S. Resta O. Carratù P. 2011Reversibility of the endothelial dysfunction after CPAP therapy in OSAS patients. 2011 Feb 24. [Epub ahead of print].
Luscher T. F. Vanhoutte P. M. 1990The endothelium: modulator of cardiovascular function. Boca Raton, FL: CRC Press, 1990.
Brunner H. Cockcroft J. R. Deanfield J. Donald A. Ferrannini E. Halcox J. Kiowski W. Luscher T. F. Mancia G. Natali A. Oliver J. J. Pessina A. C. Rizzoni D. Rossi G. P. Salvetti A. Spieker L. E. Taddei S. Webb D. J. 2005Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases: a statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension. 2005; 23 233 246.
Sowers J. R. Lester M. A. 1999Diabetes and cardiovascular disease. Diabetes Care. 1999;22(suppl 3): C14 C20.
Megnien J. L. Simon A. Andriani A. Segond P. Jeannin S. Levenson J. 1996Cholesterol lowering therapy inhibits the lowflow mediated vasoconstriction of the brachial artery in hypercholesterolemic subjects. 1996; 42 187 93.
Cohen J. D. Drury J. H. Ostdiek J. Finn J. Babu B. R. Flaker G. et al. 2000Benefits of lipid lowering on vascular reactivity in patients with coronary artery disease and average cholesterol levels: a mechanism for reducing clinical events? 2000; 139 734 8.
Plotnick G. D. Corretti M. C. Vogel R. A. 1997Effect of antioxidant vitamins on the transient impairment of endothelium-dependent brachial artery vasoactivity following a single high-fat meal. 1997; 278 1682 6.
Koh K. K. Cardillo C. Bui M. N. et al. 1999 Vascular effects of estrogen and cholesterol-lowering therapies in hypercholesterolemic postmenopausal women.1999; 99 354 60.
Wilmink H. W. Banga J. D. Hijmering M. Erkelens W. D. Stroes E. S. Rabelink T. J. 1999 Effect of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor antagonism on postprandial endothelial function.1999; 34 140 5.
Toborek M. Kaiser S. 1999 Endothelial cell functions. Relationship to atherogenesis.1999,94: 295 314.
Ludmer P. L. Selwyn A. P. Shook T. L. et al. 1986Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 1986; 315 1046 1051.
Rossi R. Chiurlia E. Nuzzo A. Cioni E. Origliani G. Modena M. G. 2004 Flow-mediated vasodilation and the risk of developing hypertension in healthy postmenopausal women.2004; 44 1636 1640.
Rossi R. Cioni E. Nuzzo A. Origliani G. Modena M. G. 2005 Endothelial-dependent vasodilation and incidence of type 2 diabetes in a population of healthy postmenopausal women.2005; 28 702 707.
Lerman A. Zeiher A. M. 2005 Endothelial function: cardiac events.2005; 111 363 8.
Joannides R. Haefeli W. E. Linder L. et al. 1995 Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo.1995; 91 1314 19.
Agewall S. Hulthe J. Fagerberg B. et al. 2002 Post-occlusion brachial artery vasodilatation after ischaemic handgrip exercise is nitric oxide mediated.2002; 22 18 23.
Pyke K. E. Tschakovsky M. E. 2005The relationship between shear stress and flow-mediated dilatation: implications for the assessment of endothelial function. J Physiol 2005; 568 357 369.
O’Rourke M. F. Nichols W. W. 2004Shear stress and flow-mediated dilation. Hypertension 2004; 44 119 120.
Sonka M. Liang W. Lauer R. M. 2002 Automated analysis of brachial ultrasound image sequences: early detection of cardiovascular disease via surrogates of endothelial function.2002; 21 1271 1279.
Takase B. Uehata A. Akima T. et al. 1998 Endothelium-dependent flow-mediated vasodilation in coronary and brachial arteries in suspected coronary artery disease.1998; 82 1535 39.
Neunteufl T. Katzenschlager R. Hassan A. et al. 1997 Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease.1997; 129 111 18.
Hirsch A. T. Haskal Z. J. Hertzer N. R. Bakal C. W. Creager M. A. Halperin J. L. Hiratzka L. F. Murphy W. R. Olin J. W. Puschett J. B. Rosenfield K. A. Sacks D. Stanley J. C. Taylor L. M. Jr. White C. J. White J. White R. A. Antman E. M. Smith S. C. Jr. Adams C. D. Anderson J. L. Faxon D. P. Fuster V. Gibbons R. J. Hunt S. A. Jacobs A. K. Nishimura R. Ornato J. P. Page R. L. Riegel B. 2006 ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; Trans Atlantic Inter-Society Consensus; and Vascular Disease Foundation. . 2006;113(11): e463 654.
Simon A. Gariepy J. Levenson J. 1997Ultrasonographic study of the arterial walls: application to the detection of preclinical atherosclerosis. Arch Mal Coeur Vaiss. 1997;90 Spec No 2, 7 10.
Astrand H. Sandgren T. Ahlgren A. R. Länne T. 2003 Noninvasive ultrasound measurements of aortic intima-media thickness: implications for in vivo study of aortic wall stress.J Vasc Surg. 2003 Jun; 37 6 1270 6.
Grimshaw G. Thompson J. 1997 Changes in diameter of the abdominal aorta with age: an epidemiological study.. 1997; 25 7 13.
Lakatta E. 2003 Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises. Part 3: Cellular and molecular clues to heart and arterial aging. 2003; 107 490 497.
Norman P. Le M. Pearce C. Jamrozik K. 2004 Infrarenal aortic diameter predicts all-cause mortality.Arterioscler Thromb Vasc Biol. 2004 Jul; 24 7 1278 82.
Freiberg M. S. Arnold A. M. Newman A. B. Edwards M. S. Kraemer K. L. Kuller L. H. 2008Abdominal aortic aneurysms, increasing infrarenal aortic diameter, and risk of total mortality and incident cardiovascular disease events: 10-year follow-up data from the Cardiovascular Health Study. Circulation. 2008 Feb 26; 117 8 1010 7.
Allison M. A. Kwan K. Di Tomasso D. Wright C. M. Criqui M. H. 2008 The epidemiology of abdominal aortic diameter. . 2008; 48 1 121 127.
Ciccone M. M. Favale S. Bhuva A. Scicchitano P. Caragnano V. Lavopa C. De Pergola G. Loverro G. 2009 Anteroposterior diameter of the infrarenal abdominal aorta is higher in women with polycystic ovary syndrome. . 2009; 5 3 561 6.
Gorter P. M. Visseren F. L. Moll F. L. van der Graaf Y. SMART Study Group 2008 Intra-abdominal fat and metabolic syndrome are associated with larger infrarenal aortic diameters in patients with clinically evident arterial disease. J Vasc Surg. 2008 Jul; 48 1 114 20.
Wilmink A. B. Quick C. R. Hubbard C. S. Day N. E. 2003Effectiveness and cost of screening for abdominal aortic aneurysm: results of a population screening program. J Vasc Surg. 2003 Jul; 38 1 72 7.
Wilmink A. B. Forshaw M. Quick C. R. Hubbard C. S. Day N. E. 2002 Accuracy of serial screening for abdominal aortic aneurysms by ultrasound.J Med Screen. 2002; 9 3 125 7.
Lederle F. A. Walker J. M. Reinke D. B. 1988 Selective screening for abdominal aortic aneurysms with physical examination and ultrasound.. 1988; 148 8 1753 1756.
Brady A. R. Gerald F. Fowkes R. Thompson S. G. Powell J. T. 2001 Aortic aneurysm diameter and risk of cardiovascular mortality.. 2001; 21 7 1203 1207.
van den Bosch M. A. van der Graaf Y. Eikelboom B. C. Algra A. Mali W. P. SMART Study Group 2001Second Manifestations of ARTerial Disease. Distal aortic diameter and peripheral arterial occlusive disease. J Vasc Surg. 2001; 34 6 1085 9.
Pleumeekers H. J. Hoes A. W. Mulder P. G. van der Does E. Hofman A. Laméris J. S. Grobbee D. E. 1998 Differences in observer variability of ultrasound measurements of the proximal and distal abdominal aorta.J Med Screen. 1998; 5 2 104 8.
Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. 1990Relationship of atherosclerosis in young men to serum lipoprotein cholesterol concentration and smoking. A preliminary report from the PDAY. 1990; 264 3018 24.
Mary J. Roman M. J. Naqvi T. Z. Gardin J. M. et al. 2006Clinical application of noninvasive vascular ultrasound in cardiovascular risk stratification: a report from the American Society of Echocardiography and the Society for Vascular Medicine and Biology. American Society of Echocardiography Report. Vasc.med. 2006; 11 201 211.
Gepner A. D. Keevil J. G. Wyman R. A. Korcarz C. E. Aeschlimann S. E. Busse K. L. et al. 2006Use of carotid intima-media thickness and vascular age to modify cardiovascular risk prediction. J Am Soc Echocardiogr 2006; 19 1170 4.
Ali Y. S. Rembold K. E. Weaver B. Wills M. B. Tatar S. Ayers C. R. et al. 2006 Prediction of major adverse cardiovascular events by age-normalized carotid intimal medial thickness. 2006; 187 186 90.
Heiss G. Sharrett A. R. Barnes R. Chambless L. E. Szklo M. Alzola C. 1991 Carotid atherosclerosis measured by B-mode ultrasound in populations: associations with cardiovascular risk factors in the ARIC study.1991; 134 250 6.
De Pergola G. Ciccone M. Pannacciulli N. Modugno M. Sciaraffia M. Minenna A. Rizzon P. Giorgino R. 2000 Lower insulin sensitivity as an independent risk factor for carotid wall thickening in normotensive, non-diabetic, non-smoking normal weight and obese premenopausal women.2000; 24 825 9.
Pannacciulli N. De Pergola G. Ciccone M. Rizzon P. Giorgino F. Giorgino R. 2003 Effect of family history of type 2 diabetes on the intima-media thickness of the common carotid artery in normal-weight, overweight, and obese glucose-tolerant young adults.. 2003; 26 1230 4.
Nagai Y. Metter J. Earley C. J. et al. 1998 Increased carotid artery intimal-medial thickness in asymptomatic older subjects with exercise-induced myocardial ischemia.1998; 98 1504 9.
Bots M. L. Hofman A. Grobbee D. E. 1994 Common carotid intima- media thickness and lower extremity arterial atherosclerosis. The Rotterdam Study. 1994; 14 1885 91.
Balbarini A. Buttitta F. Limbruno U. Petronio A. S. Baglini R. Strata G. Mariotti R. Ciccone M. Mariani M. 2000 Usefulness of carotid intima-media thickness measurement and peripheral B-mode ultrasound scan in the clinical screening of patients with coronary artery disease.. 2000; 51 269 79.
Gasparyan A. Y. 2009 The Use of Carotid Artery Ultrasonography in Different Clinical Conditions. 2009 3 78 80
Chambless L. E. Folsom A. R. Clegg L. X. 2000Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities (ARIC) Study. 2000; 151 478 87.
O’Leary D. H. Polak J. F. Kronmal R. A. Manolio T. A. Burke G. L. Wolfson S. K. Jr. 1999Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. 1999; 340 14 22.
Greenland P. Abrams J. Aurigemma G. P. et al. 2000Prevention Conference V: Beyond secondary prevention. Identifying the high-risk patient for primary prevention: noninvasive tests of atherosclerotic burden.Writing Group III. 2000; 101: E16 E22.
Kablak-Ziembicka A. Tracz W. Przewlocki T. Pieniazek P. Sokolowski A. Konieczynska M. 2004 Association of increased carotid intima-media thickness with the extent of coronary artery disease. 2004; 90 1286 90.
Iglesias del Sol A. Bots M. L. Grobbee D. E. Hofman A. Witteman J. C. 2002Carotid intimamedia thickness at different sites: relation to incident myocardial infarction; the Rotterdam Study. 2002; 23 934 40.
Pignoli P. Tremoli E. Poli A. Oreste P. Paoletti R. 1986 Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging.. 1986; 74 6 1399 406.
van Swijndregt A. D. M. 1996An in-vitro evaluation of the line pattern of the near and far walls of carotid arteries using B-mode ultrasound. Ultrasound Med Biol. 1996; 22 8 1007 1015.
Tang R. Hennig M. Thomasson B. et al. 2000 Baseline reproducibility of B-mode ultrasonic measurement of carotid artery intima-media thickness: the European Lacidipine Study on Atherosclerosis (ELSA).2000; 18 197 2018.
Touboul P. J. Vicaut E. Labreuche J. Belliard J. P. Cohen S. Kownator S. 2005Pithois-Merli Design, Baseline Characteristics and Carotid Intima-Media Thickness Reproducibility in the PARC Study. 19 57 63.