Acute Myocardial Infarction in an Adolescent Receiving Anagrelide for Essential Thrombocythemia with Underlying Persistent Coronary Endothelial Dysfunction.

Essential thrombocythemia (ET) is a Philadelphia chromosome-negative myeloproliferative disorder that is characterized by the overproduction of platelets and a marked increase in the numbers of mature megakaryocytes present in the bone marrow. Thrombohemorrhagic disorders are major morbidities of ET, especially those with mutations in the gene encoding Janus kinase 2 (JAK2). In this study, we report the case of an 18-year-old patient with ET carrying JAK2 mutation who developed acute ST-elevation myocardial infarction (STEMI) 5 months after a commencement of anagrelide. Coronary endothelial dysfunction confirmed by positive acetylcholine provocation test lasted a year after the occurrence of STEMI. Furthermore, intracoronary imaging using optical coherence tomography demonstrated non-atheromatous intimal fibrosis possibly due to chronic endothelial damage. The coronary pathologies reflected chronic change potentially associated with properties of ET and JAK2 mutation in addition to hyperviscosity. These observations suggest that the side effect of anagrelide in our patient was considered causative, while underlying chronic endothelial dysfunction and adverse endothelial remodeling may be predisposing factors to his fatal cardiovascular events.

Nonthrombotic proliferative vasculopathy associated with antiphospholipid antibodies: A case report and literature review.

A 20-year-old man presented with recurrent hemoptysis for seven months. A small subpleural nodule in his right lower lobe was found and excised surgically. Based on the presence of antiphospholipid antibodies (aPL) and vascular wall hypertrophy without vasculitis or an intraluminal thrombus, nonthrombotic proliferative vasculopathy (NTPV) affecting pulmonary arteries was diagnosed. Recently, aPL have been postulated to directly induce the proliferation of vascular cells in the intima and media, leading to NTPV. We review 5 cases of NTPV-associated aPL with critical ischemia in the lower extremities and gastrointestinal infarction. NTPV-associated aPL might be distinct from classic antiphospholipid syndrome and should be considered in aPL-positive patients who present with vascular occlusions of medium-sized vessels in the absence of atherosclerotic risk factors and systemic or local inflammation.

Endothelial Myocyte Enhancer Factor 2c Inhibits Migration of Smooth Muscle Cells Through Fenestrations in the Internal Elastic Lamina.

OBJECTIVE: Laminar flow activates myocyte enhancer factor 2 (MEF2) transcription factors in vitro to induce expression of atheroprotective genes in the endothelium. Here we sought to establish the role of Mef2c in the vascular endothelium in vivo. APPROACH AND RESULTS: To study endothelial Mef2c, we generated endothelial-specific deletion of Mef2c using Tie2-Cre or Cdh5-Cre-ERT2 and examined aortas and carotid arteries by en face immunofluorescence. We observed enhanced actin stress fiber formation in the Mef2c-deleted thoracic aortic endothelium (laminar flow region), similar to those observed in normal aortic inner curvature (disturbed flow region). Furthermore, Mef2c deletion resulted in the de novo formation of subendothelial intimal cells expressing markers of differentiated smooth muscle in the thoracic aortas and carotids. Lineage tracing showed that these cells were not of endothelial origin. To define early events in intimal development, we induced endothelial deletion of Mef2c and examined aortas at 4 and 12 weeks postinduction. The number of intimal cell clusters increased from 4 to 12 weeks, but the number of cells within a cluster peaked at 2 cells in both cases, suggesting ongoing migration but minimal proliferation. Moreover, we identified cells extending from the media through fenestrations in the internal elastic lamina into the intima, indicating transfenestral smooth muscle migration. Similar transfenestral migration was observed in wild-type carotid arteries ligated to induce neointimal formation. CONCLUSIONS: These results indicate that endothelial Mef2c regulates the endothelial actin cytoskeleton and inhibits smooth muscle cell migration into the intima.

A New Technique to Induce Experimental Myointimal Hyperplasia.

BACKGROUND: Arterial myointimal hyperplasia (MIH) has a significant impact on the long-term outcomes of vascular procedures such as bypass surgery and angioplasty. In this study, we describe a new and innovative technique to induce MIH using a dental flossing cachet in Wistar rats. METHODS: The intimal damage in the common carotid artery was induced by inserting the tip of the dental flossing cachet through the external carotid artery into the common carotid artery and turning it on for 3 rounds of 20 s each (n = 10). After 2 weeks, the rats were anesthetized and the common carotid arteries of the experimental side and the contralateral side (control) were harvested and preserved for histopathological studies. RESULTS: The experimental carotid arteries showed significant intimal proliferation and thickening compared to the controls. The intima/media ratio of the experimental and normal (control) common carotid arteries were 1.274 ± 0.162 and 0.089 ± 0.023 (mean ± SEM), respectively (p < 0.001). CONCLUSION: This technique is simple, inexpensive, and highly reproducible and it induces sufficient MIH to study this phenomenon in animal models.

Cerebral Arteriovenous Malformation Flow Is Associated With Venous Intimal Hyperplasia.

BACKGROUND AND PURPOSE: The pathogenesis of venous intimal hyperplasia and venous outflow stenosis associated with cerebral arteriovenous malformation (AVM) draining veins is poorly understood. We sought to determine the relationship between maximum vein wall thickness and AVM flow. METHODS: Patients who underwent AVM surgical resection and had flow measured before treatment using quantitative magnetic resonance angiography were retrospectively reviewed. Specimens were mounted on slides and stained with elastin special stain. Perinidal veins were identified, and maximum wall thickness was measured from digitized images. Relationship between maximum vein wall thickness and AVM flow was assessed. RESULTS: Twenty-eight patients were included. Spearman correlation revealed a statistically significant relationship between maximum vein wall thickness and total AVM flow (ρ=+0.51; P=0.006), AVM flow per draining vein (ρ=+0.41; P=0.03), and mean intranidal vessel diameter (ρ=+0.39; P=0.04). CONCLUSIONS: Maximum vein wall thickness increases with higher total AVM flow and AVM flow per draining vein. This finding implicates chronically high AVM inflow in venous intimal hyperplasia.

Fluid upstream shear stress of rabbit aortic stenosis inhibits neointimal hyperplasia by promoting endothelization after balloon injury.

BACKGROUND: Atherosclerosis is associated with disturbed blood flow characterized by low and oscillatory shear stress (SS), however, few study directly links SS to neointimal hyperplasia in animal model. This study was focused on the effects of changed SS upon the neointimal hyperplasia which responded to balloon injury in a novel rabbit model with partially-constricted abdominal aorta. METHODS: We established a rabbit model subjected to partial abdominal aortic constriction with a cylinder-shaped cannula as a model of disturbed flow, which was similar to the hemodynamic features of stenosis caused by atherosclerosis plaque. Further, balloon injury was performed to investigate the relationship between SS and neointimal hyperplasia. Four weeks later, the abdominal aorta was assessed with digital subtraction angiography (DSA) and intravascular ultrasound (IVUS). The vascular sections were embedded in paraffin blocks for morphometric analysis to evaluate neointimal hyperplasia, and anti-CD31 immunohistochemical staining was for endothelialization ratio. RESULTS: In upstream the stenosis, the changed SS leads to neointimal hyperplasia compared with normal SS (11,729 ± 1205 vs 8418 ± 737, P = 0.023). However, the upstream SS of the stenosis can promote vascular re-endothelialization after balloon injury compared with normal SS, verified by endothelialization ratio (0.36 ± 0.03 vs 0.32 ± 0.03, P = 0.017), thereby attenuate neointimal hyperplasia (64,851 ± 3995 vs 68,335 ± 3867, P = 0.018). CONCLUSION: The upstream SS of stenosis, not downstream SS, inhibits the neointimal hyperplasia after balloon injury by promoting vascular re-endothelializtion.

[Effekt of blood flow shutdown on the vein damage when exposed to HIFU].

The purpose. In the study we investigated the impact of the partial blood flow shutdown on structural changes in the rabbit vena cava posterior wall after exposure to high-intensity focused ultrasound (HIFU). Methods. Ultrasound Exposure: frequency of 1.65 MHz, the ultrasound intensity in the focus of 13.6 kW/cm2, the area of the focal spot 1 mm2, continuous ultrasound, exposure for 3 seconds. Results. Immediately after HIFU exposure all layers of the vein wall showed characteristic signs of thermal damage. A week after exposure structural changes in the intima, media and adventitia was minimal in the part of vessel with preserved blood flow, and after 4 weeks the changes were not revealed. A week after HIFU exposure partial endothelium destruction, destruction of myocytes, disorganization and consolidation of collagen fibers of the adventitia were observed in an isolated segment of the vessel, and in 4 weeks endothelium restored and signs of damage in media and adventitia persisted, but were less obvious than in a week after exposure. Conclusion. The shutdown of blood flow after exposure to HIFU promotes persistent changes in the vein wall. Vein compression appears to be necessary for the obliteration of the vessel, when using HIFU-technology.

Low-density lipoprotein transport through an arterial wall under hypertension - A model with time and pressure dependent fraction of leaky junction consistent with experiments.

The influence of hypertension on low-density lipoproteins intake into the arterial wall is an important factor for understanding mechanisms of atherosclerosis. It has been experimentally observed that the increased pressure leads to the higher level of the LDL inside the wall. In this paper we attempt to construct a model of the LDL transport which reproduces quantitatively experimental outcomes. We supplement the well-known four-layer arterial wall model to include two pressure induced effects: the compression of the intima tissue and the increase of the fraction of leaky junctions. We demonstrate that such model can reach the very good agreement with experimental data.

Aquaporin-1 shifts the critical transmural pressure to compress the aortic intima and change transmural flow: theory and implications.

Transmural-pressure (ΔP)-driven plasma advection carries macromolecules into the vessel wall, the earliest prelesion atherosclerotic event. The wall's hydraulic conductivity, LP, the water flux-to-ΔP ratio, is high at low pressures, rapidly decreases, and remains flat to high pressures (Baldwin AL, Wilson LM. Am J Physiol Heart Circ Physiol 264: H26-H32, 1993; Nguyen T, Toussaint, Xue JD, Raval Y, Cancel CB, Russell LM, Shou S, Sedes Y, Sun O, Yakobov Y, Tarbell JM, Jan KM, Rumschitzki DS. Am J Physiol Heart Circ Physiol 308: H1051-H1064, 2015; Tedgui A, Lever MJ. Am J Physiol Heart Circ Physiol. 247: H784-H791, 1984. Shou Y, Jan KM, Rumschitzki DS. Am J Physiol Heart Circ Physiol 291: H2758-H2771, 2006) due to pressure-induced subendothelial intima (SI) compression that causes endothelial cells to partially block internal elastic laminar fenestrae. Nguyen et al. showed that rat and bovine aortic endothelial cells express the membrane protein aquaporin-1 (AQP1) and transmural water transport is both transcellular and paracellular. They found that LP lowering by AQP1 blocking was perplexingly ΔP dependent. We hypothesize that AQP1 blocking lowers average SI pressure; therefore, a lower ΔP achieves the critical force/area on the endothelium to partially block fenestrae. To test this hypothesis, we improve the approximate model of Huang et al. (Huang Y, Rumschitzki D, Chien S, Weinbaum SS. Am J Physiol Heart Circ Physiol 272: H2023-H2039, 1997) and extend it by including transcellular AQP1 water flow. Results confirm the observation by Nguyen et al.: wall LP and water transport decrease with AQP1 disabling. The model predicts 1) low-pressure LP experiments correctly; 2) AQP1s contribute 30-40% to both the phenomenological endothelial + SI and intrinsic endothelial LP; 3) the force on the endothelium for partial SI decompression with functioning AQP1s at 60 mmHg equals that on the endothelium at ∼43 mmHg with inactive AQP1s; and 4) increasing endothelial AQP1 expression increases wall LP and shifts the ΔP regime where LP drops to significantly higher ΔP than in Huang et al. Thus AQP1 upregulation (elevated wall LP) might dilute and slow low-density lipoprotein binding to SI extracellular matrix, which may be beneficial for early atherogenesis.

Aortic dissection simulation models for clinical support: fluid-structure interaction vs. rigid wall models.

BACKGROUND: The management and prognosis of aortic dissection (AD) is often challenging and the use of personalised computational models is being explored as a tool to improve clinical outcome. Including vessel wall motion in such simulations can provide more realistic and potentially accurate results, but requires significant additional computational resources, as well as expertise. With clinical translation as the final aim, trade-offs between complexity, speed and accuracy are inevitable. The present study explores whether modelling wall motion is worth the additional expense in the case of AD, by carrying out fluid-structure interaction (FSI) simulations based on a sample patient case. METHODS: Patient-specific anatomical details were extracted from computed tomography images to provide the fluid domain, from which the vessel wall was extrapolated. Two-way fluid-structure interaction simulations were performed, with coupled Windkessel boundary conditions and hyperelastic wall properties. The blood was modelled using the Carreau-Yasuda viscosity model and turbulence was accounted for via a shear stress transport model. A simulation without wall motion (rigid wall) was carried out for comparison purposes. RESULTS: The displacement of the vessel wall was comparable to reports from imaging studies in terms of intimal flap motion and contraction of the true lumen. Analysis of the haemodynamics around the proximal and distal false lumen in the FSI model showed complex flow structures caused by the expansion and contraction of the vessel wall. These flow patterns led to significantly different predictions of wall shear stress, particularly its oscillatory component, which were not captured by the rigid wall model. CONCLUSIONS: Through comparison with imaging data, the results of the present study indicate that the fluid-structure interaction methodology employed herein is appropriate for simulations of aortic dissection. Regions of high wall shear stress were not significantly altered by the wall motion, however, certain collocated regions of low and oscillatory wall shear stress which may be critical for disease progression were only identified in the FSI simulation. We conclude that, if patient-tailored simulations of aortic dissection are to be used as an interventional planning tool, then the additional complexity, expertise and computational expense required to model wall motion is indeed justified.

Bifurcation and dynamics in a mathematical model of early atherosclerosis: How acute inflammation drives lesion development.

We present here a mathematical model describing the primary mechanisms that drive the early stages of atherosclerosis. This involves the interactions between modified low density lipoprotein (LDL), monocytes/macrophages, cytokines and foam cells. This model suggests that there is an initial inflammatory phase associated with atherosclerotic lesion development and a longer, quasi-static process of plaque development inside the arterial wall that follows the initial transient. We will show results that show how different LDL concentrations in the blood stream and different immune responses can affect the development of a plaque. Through numerical bifurcation analysis, we show the existence of a fold bifurcation when the flux of LDL from the blood is sufficiently high. By analysing the model presented in this paper, we gain a greater insight into this inflammatory response qualitatively and quantitatively.

Effects of wall shear stress in venous neointimal hyperplasia of arteriovenous fistulae.

AIM: An arteriovenous fistulae (AVF) is the preferred vascular access for maintenance haemodialysis patients. Its dysfunction is often due to venous stenosis, which is mainly caused by neointimal hyperplasia. Additionally, haemodynamic forces, especially wall shear stress (WSS), as a mechanical stimuli to venous wall have a significant role in neointimal hyperplasia. The purpose of this study was to evaluate the association between WSS and neointimal hyperplasia. METHODS: An 'end-to-side' AVF was created between the right femoral artery and vein of canines. Canines were killed at 7 and 28 days post-surgery. The velocity and WSS in the three-dimensional computational model of AVF were simulated using computational fluid dynamics (CFDs). The four typical sites of the vein evaluated in this study, chosen according to the haemodynamic analysis, included the arteriovenous anastomosis (A-V), the juxta-anastomotic segment (J-V), the juxta-ligation segment (L-V) and the proximal vein (P-V). The specimens were haematoxylin-eosin stained and the intima-media thickening was then measured. RESULTS: Neointimal hyperplasia was more obvious in the inner wall of the J-V and L-V (low-and-disturbed WSS) sites compared with the P-V and A-V sites, and the outer wall of the L-V and J-V segments (high or laminar WSS) (P < 0.01). CONCLUSION: In this study, we described the haemodynamic condition in the AVF and found that neointimal hyperplasia predisposed to occur in the inner wall of venous segment near the anastomosis. We also found that not only the neointimal hyperplasia has a strong inverse correlation with WSS levels, but also is related to flow patterns.

Medial vascular calcification revisited: review and perspectives.

Vascular calcifications (VCs) are actively regulated biological processes associated with crystallization of hydroxyapatite in the extracellular matrix and in cells of the media (VCm) or intima (VCi) of the arterial wall. Both patterns of VC often coincide and occur in patients with type II diabetes, chronic kidney disease, and other less frequent disorders; VCs are also typical in senile degeneration. In this article, we review the current state of knowledge about the pathology, molecular biology, and nosology of VCm, expand on potential mechanisms responsible for poor prognosis, and expose some of the directions for future research in this area.

Intima modifier locus 2 controls endothelial cell activation and vascular permeability.

Carotid intima formation is a significant risk factor for cardiovascular disease. C3H/FeJ (C3H/F) and SJL/J (SJL) inbred mouse strains differ in susceptibility to immune and vascular traits. Using a congenic approach we demonstrated that the Intima modifier 2 (Im2) locus on chromosome 11 regulates leukocyte infiltration. We sought to determine whether inflammation was due to changes in circulating immune cells or activation of vascular wall cells in genetically pure Im2 (C3H/F.SJL.11.1) mice. Complete blood counts showed no differences in circulating monocytes between C3H/F and C3H/F.SJL.11.1 compared with SJL mice. Aortic vascular cell adhesion molecule-1 (VCAM-1) total protein levels were dramatically increased in SJL and C3H/F.SJL.11.1 compared with C3H/F mice. Immunostaining of aortic endothelial cells (EC) showed a significant increase in VCAM-1 expression in SJL and C3H/F.SJL.11.1 compared with C3H/F under steady flow conditions. Immunostaining of EC membranes revealed a significant decrease in EC size in SJL and C3H/F.SJL.11.1 vs. C3H/F in regions of disturbed flow. Vascular permeability was significantly higher in C3H/F.SJL.11.1 compared with C3H/F. Our results indicate that Im2 regulation of leukocyte infiltration is mediated by EC inflammation and permeability. RNA sequencing and pathway analyses comparing genes in the Im2 locus to C3H/F provide insight into candidate genes that regulate vascular wall inflammation and permeability highlighting important genetic mechanisms that control vascular intima in response to injury.

Long term impact of balloon post-dilatation on neointimal formation: an experimental comparative study between second-generation self-expanding versus balloon-expandable stent technologies.

Background: Self-expanding stents (SES) are reemerging as therapeutic alternatives to treat coronary artery disease. It has been proposed that SES can improve clinical outcomes by inducing less injury at implantation and achieving better vessel wall apposition.To date, little data exists comparing the vascular response to both methods of deployment in a controlled experimental setting. Objective: To quantify differences in vascular injury and healing between second-generation SES and balloon-expandable stents (BES) and the effects of balloon post-dilatation in a porcine coronary model. Methods: Seventy-five bare SES (AXXESS or vProtect) and 42 BES (Vision) were implanted in porcine coronaries. A subset of these received balloon post-dilatation(SES 1 D 5 22, BES 1 D 5 20). Follow-up was scheduled at 30 (BES 5 10, BES 1 D 56, SES 5 19, SES 1 D 5 8), 90 (BES 5 6, BES 1 D 5 8, SES 5 19, SES 1 D 5 8), and 180 days (BES 5 6, BES 1 D 5 6, SES 5 15, SES 1 D 5 6). Results: In vivo imaging and histological analysis showed that neointimal formation peaks early (30 days) in BES. Conversely, for SES, the peak occurred later (90 days). However, the neointimal formation achieved in either group equalized at 180 days. For SES, post-dilatation shortened the peak of neointimal formation to 30 days. Conversely, for BES, post-dilatation delayed the peak of neointimal formation to 90 days. At 30 days, histology showed that SES had significantly less injury. However, at 90 days, injury scores tended to be higher for SES. By 180 days, injury scores were comparable between both groups. Conclusions: The mechanism of stent expansion influences the degree of vascular injury and healing. The synergistic use of balloon post dilatation changes the dynamics of healing and may impact the potential beneficial effects inherent to SES technologies.

Borderline ankle-brachial index value of 0.91-0.99 is associated with endothelial dysfunction.

BACKGROUND: An ankle-brachial index (ABI) value of 0.91-0.99 is considered borderline and associated with an increased risk of cardiovascular events. However, there is no information on the relationship between borderline ABI and endothelial function. METHODS AND RESULTS: We measured ABI and assessed vascular function by flow-mediated vasodilation (FMD) and nitroglycerin-induced vasodilation in 389 subjects who underwent health examinations. Subjects were divided into 3 groups according to ABI (normal group: 1.00-1.40, borderline group: 0.91-0.99, abnormal group: ≤0.90 or >1.40). FMD was significantly smaller in both the borderline and the abnormal group than in the normal group. There was no significant difference in the vascular responses to nitroglycerin between the normal and borderline groups. Vascular response to nitroglycerin was significantly higher in the normal group than in the abnormal group. Borderline and abnormal ABI values were significantly associated with an increased odds ratio of low tertile of FMD levels, using the normal ABI group as the reference. Multiple logistic regression analysis for FMD revealed that age, sex, hypertension, diabetes mellitus, and borderline ABI independently remained associated with FMD. CONCLUSIONS: ABI of 0.91-0.99 is associated with endothelial dysfunction. ABI examination is a simple and cost-effective method for obtaining the additional information on the initial step of atherosclerosis beyond the assessment of peripheral artery disease.

Proinflammation of aging central arteries: a mini-review.

Arterial aging is a cornerstone of organismal aging. The central arterial wall structurally and functionally remodels under chronic proinflammatory stress over a lifetime. The low-grade proinflammation that accompanies advancing age causes arterial wall thickening and stiffening. These structural and functional alterations are consequences of adverse molecular and cellular events, e.g. an increase in local angiotensin II signaling that induces an inflammatory phenotypic shift of endothelial and smooth muscle cells. Thus, interventions to restrict proinflammatory signaling are a rational approach to delay or prevent age-associated adverse arterial remodeling.

Strain-blood pressure index for evaluation of early changes in elasticity of anterior tibial artery in patients with type 2 diabetes mellitus.

BACKGROUND: The aim of this study was to investigate the feasibility and value of strain-blood pressure index (SBPI) to assess early changes in elasticity of anterior tibial artery in patients with type 2 diabetes mellitus (T2DM). MATERIAL/METHODS: Eighty-one randomly selected in-patients with T2DM were divided into 2 groups--a vascular complication negative group (n=42) and a vascular complication positive group (n=39). Forty healthy volunteers were enrolled in a control group. Ultrasonographic scans using Xstrain™ technique were conducted for every patient to obtain the maximum circumferential strain (CSmax) of anterior tibial artery; patient blood pressure was also measured for calculating strain-blood pressure index (SBPI=CSmax/[(local pulse pressure)/local diastolic blood pressure] ×100%. Afterwards, SBPIs of various groups were comparatively analyzed. RESULTS: Differences in SBPIs among the 3 groups were statistically significant (control group > negative group > positive group, P<0.05). CONCLUSIONS: SBPI could be used as a new indicator for the evaluation on the anterior tibial arterial elasticity of T2DM patients and it was able to reflect the early elasticity changes in anterior tibial arteries in T2DM patients with atherosclerosis.

Vascular calcification in chronic renal failure: what have we learned from animal studies?

Accelerated atherosclerotic plaque calcification and extensive medial calcifications are common and highly detrimental complications of chronic kidney disease. Valid murine models have been developed to investigate both pathologically distinguishable complications, which allow for better insight into the cellular mechanisms underlying these vascular pathologies and evaluation of compounds that might prevent or retard the onset or progression of vascular calcification. This review describes various experimental models that have been used for the study of arterial intimal and/or medial calcification and discusses the extent to which this experimental research has contributed to our current understanding of vascular calcification, particularly in the setting of chronic renal failure.

Intima-media thickness of brachial artery, vascular function, and cardiovascular risk factors.

OBJECTIVE: Cardiovascular diseases are associated with impaired flow-mediated vasodilation (FMD) and increase in carotid intima-media thickness (IMT). Both FMD and IMT are independent predictors for cardiovascular outcomes. When measuring FMD and nitroglycerine-induced vasodilation in the brachial artery, IMT can also be simultaneously assessed in the same brachial artery. The purpose of this study was to determine the relationships between IMT of the brachial artery, vascular function, and cardiovascular risk factors. METHODS AND RESULTS: We measured brachial IMT, FMD, and nitroglycerine-induced vasodilation by ultrasound in 388 subjects who underwent health examination (mean age, 45±22 years; age range, 19-86), including patients with cardiovascular diseases. Univariate regression analysis revealed that brachial IMT significantly correlated with age (r=0.71; P<0.001), body mass index (r=0.27; P<0.001), systolic blood pressure (r=0.40; P<0.001), diastolic blood pressure (r=0.31; P<0.001), heart rate (r=0.15; P=0.002), glucose level (r=0.18; P=0.01), and smoking pack-years (r=0.42; P<0.001), as well as Framingham risk score, a cumulative cardiovascular risk index for heart attack (r=0.49; P<0.001). FMD and nitroglycerine-induced vasodilation were inversely associated with brachial IMT (r=-0.39, P<0.001; r=-0.32, P<0.001, respectively). In addition, there was a significant relationship between brachial IMT and carotid IMT (r=0.58; P<0.001). Multivariate analysis revealed that age, sex, hypertension, and brachial artery diameter were independent predictors of brachial IMT. CONCLUSIONS: These findings suggest that brachial IMT may be a marker of the grade of atherosclerosis and may be used as a marker of vascular function, providing additive information for stratifying subjects with cardiovascular risk factors.