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Hepatic sinusoid endothelial dysfunction plays a role in hyperbilirubinemia in patients following implantation of an LVAD.

To clarify the mechanism of hyperbilirubinemia in the setting of a left ventricular assist device (LVAD), the change in hepatocellular function, hepatic sinusoid endothelial microcirculation, and inflammatory response before and after LVAD implantation were evaluated. Eight consecutive patients underwent the placement of an LVAD, and serum levels of total bilirubin (TB), transaminases [alanine transaminase (ALT), aspartate transaminase (AST)], interleukin (IL-6, IL-8), and hyaluronic acid (HA), an indicator of hepatic sinusoidal circulation, were measured before and after LVAD implantation. The TB of all patients increased significantly in the first post operative week (p < 0.05 vs. pre-operatively). In five patients, the elevated TB (4.6 +/- 4.1 mg/dl) returned to pre-operative levels (2.7 +/- 2.0 mg/dl) by the 14th post operative day (Group R), but in the other three patients who died of multiple organ failure, the level of TB increased to 39.9 +/- 16.4 mg/dl (Group A). Levels of HA and IL-8 had good correlation with the level of TB (HA: r = 0.60, p < 0.05; IL-8: r = 0.55, p < 0.05). However, AST, ALT, and IL-6 were not related to changes in TB. These results suggest that hepatic sinusoid endothelial dysfunction and inflammatory reaction may play a significant role in hepatic failure in patients following implantation of an LVAD.

Adult↗
PubMed2002

Cellular glutathione peroxidase deficiency and endothelial dysfunction.

Cellular glutathione peroxidase (GPx-1) is the most abundant intracellular isoform of the GPx antioxidant enzyme family. In this study, we hypothesized that GPx-1 deficiency directly induces an increase in vascular oxidant stress, with resulting endothelial dysfunction. We studied vascular function in a murine model of homozygous deficiency of GPx-1 (GPx-1(-/-)). Mesenteric arterioles of GPx-1(-/-) mice demonstrated paradoxical vasoconstriction to beta-methacholine and bradykinin, whereas wild-type (WT) mice showed dose-dependent vasodilation in response to both agonists. One week of treatment of GPx-1(-/-) mice with L-2-oxothiazolidine-4-carboxylic acid (OTC), which increases intracellular thiol pools, resulted in restoration of normal vascular reactivity in the mesenteric bed of GPx-1(-/-) mice. We observed an increase of the isoprostane iPF(2alpha)-III, a marker of oxidant stress, in the plasma and aortas of GPx-1(-/-) mice compared with WT mice, which returned toward normal after OTC treatment. Aortic sections from GPx-1(-/-) mice showed increased binding of an anti-3-nitrotyrosine antibody in the absence of frank vascular lesions. These findings demonstrate that homozygous deficiency of GPx-1 leads to impaired endothelium-dependent vasodilator function presumably due to a decrease in bioavailable nitric oxide and to increased vascular oxidant stress. These vascular abnormalities can be attenuated by increasing bioavailable intracellular thiol pools.

Animals↗
PubMed2006

Interleukin-6 correlates with endothelial dysfunction in young post-myocardial infarction patients.

BACKGROUND: The estimation of coronary risk based on consideration of classical risk factors is insufficient in young patients with myocardial infarction who have low expressions of classical risk factors. Endothelial dysfunction (ED) and markers of vascular inflammation may be more appropriate for risk estimation. The relations among ED and inflammation markers in such patients have not yet been explored. PATIENTS AND METHODS: Twenty-one patients (on average 44 years old) in the stable phase after myocardial infarction, with low expressions of risk factors, were included in the study. The control group consisted of 25 healthy age-matched males. ED was estimated by ultrasound measurement of the endothelium-dependent dilatation of the brachial artery. The following inflammation markers were measured: hsCRP, interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), ICAM-1, VCAM-1, selectin-P and selectin-E. RESULTS: Patients had a significantly reduced level of endothelium-dependent vasodilatation (5.6 +/- 3.5 vs. 8.8 +/- 6.5%, p < 0.05), and an increased level of IL-6 (3.2 [1.5-8.4] vs. 1.4 [0.9-2.3] ng/ml; p < 0.01). All other inflammation markers were comparable to controls. We found a significant negative correlation between ED and the levels of IL-6 (r = -0.54, p = 0.012). CONCLUSION: It appears that IL-6 is the most valuable circulating marker of ED, and consequently a useful marker of coronary risk.

Adult↗
PubMed2006

[The influence of hyperventilation in combination with active orthostasis on the condition of vegetative homeostasis in young men with atherosclerosis risk factors and endothelial dysfunction].

The aim of the study was to evaluate the effects of hyperventilation test (HVT), active orthostatic position test (AOPT), and their combination on the vegetative homeostasis in male students with risk factors of atherosclerosis (RFA) and endothelial dysfunction (ED). The mentioned tests and their combination were performed in 142 male students with RFA and ED, and 54 male students without them during brachial arterial rheovasography and cardiointervalography. Hyperactivation of the central regulatory circuit and a spastic hemodynamic condition at rest were found in subjects with FRA and ED. The sympathetic functional reserve was overstrained according to AOPT, distinctly decreased according to HVT, and exhausted when both tests were performed. The combination of HVT and AOPT is an informative stress test for pre-clinical evaluation of disturbances in adaptation mechanisms and vegetative homeostasis tensity in young men with RFA and ED. A "high value" of adaptation and the vegetative homeostasis overstrain in male students with FRA and ED indicate a premorbid condition in them.

Adolescent↗
PubMed1994

Ischemic preconditioning protects against coronary endothelial dysfunction induced by ischemia and reperfusion.

BACKGROUND: Repetitive, brief periods of ischemia and reperfusion ("preconditioning") increase the resistance of myocardial tissue to subsequent prolonged ischemic episodes and limit infarct size. We investigated whether preconditioning also protects against coronary endothelial dysfunction induced by ischemia and reperfusion. METHODS AND RESULTS: Experiments were performed in four groups of rats (n = 8 in each group): group 1 rats underwent sham surgery, group 2 rats were subjected to 20 minutes of left coronary artery occlusion without reperfusion, group 3 rats underwent 20 minutes of occlusion followed by 1 hour of reperfusion, and group 4 rats (preconditioning group) underwent the same protocol as group 3 rats, preceded by three cycles of 5 minutes of ischemia and 5 minutes of reperfusion. At the end of the experiments, coronary segments (internal diameter, 250 to 300 microns) were removed distal to the occlusion site and mounted in wire myographs for isometric tension recording. Relaxations induced by increasing concentrations of acetylcholine, the calcium ionophore A23187, or the nitric oxide (NO) donor SIN-1 were determined in arteries precontracted by serotonin. Basal NO release was estimated by measuring contractions to NG-nitro L-arginine methyl ester (L-NAME). In addition, we determined the effect of preconditioning on infarct size in two additional groups that were subjected to the same protocols as those of groups 3 and 4. In those animals, area at risk (India ink injection) and infarct size (triphenyltetrazolium stain) were determined by computerized analysis of enlarged sections after video acquisition. Preconditioning markedly limited infarct size (percent of area at risk: controls, 57 +/- 2; preconditioning, 2.2 +/- 0.6; P < .01). Ischemia (without or with reperfusion) or preconditioning did not affect the coronary responses to L-NAME, serotonin, A23187, or SIN-1. Ischemia without reperfusion did not modify the relaxations to acetylcholine (maximal relaxation: sham, 58 +/- 4%; ischemia, 56 +/- 7%; P = NS). In contrast, ischemia followed by reperfusion markedly impaired the response to acetylcholine (26 +/- 6%; P < .01 versus sham). This impaired response was restored by preconditioning (maximal relaxation: 59 +/- 9%; P = NS versus sham; P < .01 versus ischemia/reperfusion). CONCLUSIONS: In addition to protecting myocardial cells, preconditioning also protects coronary endothelial cells against ischemia/reperfusion injury.

Acetylcholine↗
PubMed2000

Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension.

Therapeutic strategies against free radicals have mostly focused on the augmentation of antioxidant defenses (eg, vitamins C and E). A novel approach is to prevent free radical generation by the enzyme system xanthine oxidase. We examined whether the inhibition of xanthine oxidase with allopurinol can improve endothelial function in subjects with type 2 diabetes and coexisting mild hypertension compared with control subjects of a similar age. We examined 23 subjects (11 patients with type 2 diabetes and 12 healthy age-matched control subjects) in 2 parallel groups. The subjects were administered 300 mg allopurinol in a randomized, placebo-controlled study in which both therapies were administered for 1 month. Endothelial function was assessed with bilateral venous occlusion plethysmography, in which the forearm blood flow responses to intra-arterial infusions of endothelium-dependent and -independent vasodilators were measured. Allopurinol significantly increased the mean forearm blood flow response to acetylcholine by 30% (3.16+/-1.21 versus 2.54+/-0.76 mL. 100 mL(-1). min(-1) allopurinol versus placebo; P=0.012, 95% CI 0.14, 1.30) but did not affect the nitroprusside response in patients with type 2 diabetes. There was no significant impact on either endothelium-dependent or -independent vascular responses in age-matched control subjects. Allopurinol improved endothelial function to near-normal levels. Regarding markers of free radical activity, the level of malondialdehyde was significantly reduced (0.30+/-0.04 versus 0. 34+/-0.05 micromol/L for allopurinol versus placebo, P=0.03) in patients with type 2 diabetes but not in control subjects. The xanthine oxidase inhibitor allopurinol improves endothelial dysfunction in patients with type 2 diabetes with mild hypertension but not in matched control subjects. In the former group, allopurinol restored endothelial function to near-normal levels.

Age Factors↗
PubMed2006

Acarbose, an alpha-glucosidase inhibitor, improves endothelial dysfunction in Goto-Kakizaki rats exhibiting repetitive blood glucose fluctuation.

Several epidemiological studies have revealed that subjects with postprandial hyperglycemia are at increased risk of cardiovascular disease. However, the impact of postprandial hyperglycemia and its treatment on endothelial function has not been clarified yet. In this study, Goto-Kakizaki (GK) rats, a non-obese type 2 diabetes model, fed twice daily were used as a model of repetitive postprandial glucose spikes. We investigated the endothelial function in these rats treated or untreated with acarbose, an alpha-glucosidase inhibitor. Administration of acarbose for 12 weeks markedly improved postprandial hyperglycemia, postprandial insulin level, total cholesterol, triglyceride, and free fatty acid level in GK rats. Furthermore, acarbose efficiently reduced the number of monocytes adherent to aortic endothelial layer, improved acetylcholine-dependent vasodilatation, and reduced intimal thickening of the aorta. While it is generally regarded that repetitive postprandial hyperglycemia is associated with the onset of cardiovascular diseases, our data demonstrated that acarbose treatment efficiently ameliorated endothelial dysfunction and reduced intimal thickening, thus adding support to the protective effect of acarbose against the onset of cardiovascular disease.

Acarbose↗
PubMed2004

Successful treatment of symptomatic coronary endothelial dysfunction with enhanced external counterpulsation.

Enhanced external counterpulsation (EECP) is a valuable therapeutic option for patients with coronary artery disease and refractory angina. Although the exact mechanisms by which this technique exerts favorable effects remain unclear, improvement in endothelial function is considered a potential mechanism contributing to the clinical benefit associated with EECP. We describe a young woman with severely symptomatic coronary endothelial dysfunction in the absence of obstructive coronary artery disease who experienced a dramatic and sustained reduction in symptoms in response to a standard 35-hour course of EECP.

Adult↗
PubMed2003

[Pharmacological modulation of NO synthesis in patients with arterial hypertension and endothelial dysfunction].

An open, comparative, cross-over 8-week trial of beta-blockers nebivolol and metoprolol in 30 patients with arterial hypertension (AH) studied the office, ambulatory blood pressure and heart rate levels, endothelium-dependent vasorelaxation, endothelial NOS and NO production. It was found that nebivolol activated the system eNOS-NO and improved vasomotor parameters of the endothelium. Metoprolol failed to activate enzyme eNOS activity and NO production to the same level and did not improve the endothelial vasomotor function. The antihypertensive activity of nebivolol was higher than that of metoprolol. Thus, nebivolol can be used in patients with AH and cardiovascular risk factors to correct endothelial dysfunction.

Adrenergic beta-Antagonists↗
PubMed2001

Diabetic endothelial dysfunction: role of reactive oxygen and nitrogen species production and poly(ADP-ribose) polymerase activation.

Peroxynitrite and hydroxyl radicals are potent initiators of DNA single-strand breakage, which is an obligatory stimulus for the activation of the nuclear enzyme poly(ADP ribose) polymerase (PARP). In response to high glucose incubation medium in vitro, or diabetes and hyperglycemia in vivo, reactive nitrogen and oxygen species generation occurs. These reactive species trigger DNA single-strand breakage, which induces rapid activation of PARP. PARP in turn depletes the intracellular concentration of its substrate, NAD+, slowing the rate of glycolysis, electron transport, and ATP formation. This process results in acute endothelial dysfunction in diabetic blood vessels. Accordingly, inhibitors of PARP protect against endothelial injury under these conditions. In addition to the direct cytotoxic pathway regulated by DNA injury and PARP activation, PARP also appears to modulate the course of inflammation by regulating the activation of nuclear factor kappaB, and the expression of a number of genes, including the gene for intercellular adhesion molecule 1 and the inducible nitric oxide synthase. The research into the role of PARP in diabetic vascular injury is now supported by novel tools, such as new classes of potent inhibitors of PARP and genetically engineered animals lacking the gene for PARP. Pharmacological inhibition of PARP emerges as a potential approach for the experimental therapy of diabetic vascular dysfunction.

Animals↗
PubMed2003

Hiv Tat protein causes endothelial dysfunction in porcine coronary arteries.

PURPOSE: Human immune deficiency virus (HIV) infection is often associated with chronic diseases, including atherosclerosis. However, the molecular mechanisms are largely unknown. We examined the effect of Tat protein, an HIV regulatory protein, on endothelial function in porcine coronary arteries. METHODS: Porcine coronary arteries were dissected from nine pig hearts and cut into 5-mm ring segments, which were incubated as controls or with Tat protein (10(-7), 10(-9), 10(-11) mol/L) or Tat protein plus anti-Tat antibody, for 24 hours. Myography was performed with thromboxane A(2) analog U46619 (10 (-7) mol/L) for contraction and with graded doses of bradykinin (10(-8), 10(-7), and 10(-6) mol/L) or sodium nitroprusside (10(-5) mol/L) for relaxation. Endothelial nitric oxide synthase (eNOS) messenger RNA was determined with reverse transcriptase polymerase chain reaction (RT-PCR), and protein levels were determined with Western blot analysis. Immunoreactivity of eNOS of treated rings was also detected. RESULTS: Endothelium-dependent vasorelaxation (10-7 mol/L of bradykinin) was significantly reduced (46.41%) in pig coronary artery rings treated with 10(-7) mol/L of Tat protein, as compared with control arteries (P <.05). Arteries treated with Tat protein plus anti-Tat antibody relaxed similarly as control arteries. There were no differences in smooth muscle contractility (U46619) or endothelium-independent vasorelaxation (sodium nitroprusside) between control and Tat protein-treated groups. RT-PCR for eNOS mRNA showed reduction in eNOS levels for Tat-treated coronary artery rings by 73%, as compared with control vessels (P <.05). Tat protein-treated vessels demonstrated substantially less eNOS protein band intensity and immunoreactivity compared with control vessels. CONCLUSIONS: Tat protein significantly decreased endothelium-dependent vasorelaxation and eNOS mRNA and protein expression in endothelial cells of porcine coronary arteries. This study suggests that Tat protein-mediated endothelial dysfunction may be important in coronary heart disease in HIV-infected patients.

Animals↗
PubMed1991

L-arginine does not restore endothelial dysfunction in atherosclerotic rabbit aorta in vitro.

Bioassay studies suggest that impaired endothelium-dependent relaxation in atherosclerotic arteries is due to a reduced release of biologically active endothelium-derived relaxing factor (EDRF). We tested the hypothesis that endothelial dysfunction is caused by deficiency of the EDRF precursor L-arginine. Aortae from normal and cholesterol-fed (1%, 4 months) rabbits were excised and incubated for 1 h with 5 mM L-arginine. Pretreatment with L-arginine had no effect on the relaxation to acetylcholine in normal vessels and was without effect on the impaired response of atherosclerotic arteries to acetylcholine. This finding suggests that L-arginine deficiency is unlikely the underlying cause of impaired endothelium-dependent relaxation in the aorta of cholesterol-fed rabbits.

Acetylcholine↗
PubMed2000

Mental stress induces transient endothelial dysfunction in humans.

BACKGROUND: Mental stress has been linked to increased morbidity and mortality in coronary artery disease and to atherosclerosis progression. Experimental studies have suggested that damage to the endothelium may be an important mechanism. METHODS AND RESULTS: Endothelial function was studied in 10 healthy men (aged 50. 4+/-9.6 years) and in 8 non-insulin-dependent diabetic men (aged 52. 0+/-7.2 years). Brachial artery flow-mediated dilation (FMD, endothelium dependent) and response to 50 microg of sublingual glyceryl trinitrate (GTN, endothelium independent) were measured noninvasively by use of high-resolution ultrasound before and after (30, 90, and 240 minutes) a standardized mental stress test. The same protocol without mental stress was repeated on a separate occasion in the healthy men. In healthy subjects, FMD (5.0+/-2.1%) was significantly (P:<0.01) reduced at 30 and 90 minutes after mental stress (2.8+/-2.3% and 2.3+/-2.4%, respectively) and returned toward normal after 4 hours (4.1+/-2.0%). Mental stress had no effect on the response to GTN. In the repeated studies without mental stress, FMD did not change. The diabetic subjects had lower FMD than did the control subjects (3.0+/-1.5% versus 5.0+/-2.1%, respectively; P:=0.02) but showed no changes in FMD (2.7+/-1.1% after 30 minutes, 2.8+/-1.9% after 90 minutes, and 3.1+/-2.3% after 240 minutes) or GTN responses after mental stress. CONCLUSIONS: These findings suggest that brief episodes of mental stress, similar to those encountered in everyday life, may cause transient (up to 4 hours) endothelial dysfunction in healthy young individuals. This might represent a mechanistic link between mental stress and atherogenesis.

Adult↗
PubMed2002

Angiotensin-converting enzyme inhibition and endothelin antagonism for endothelial dysfunction in heart failure: mono-or combination therapy.

The effect of angiotensin-converting enzyme (ACE) inhibition and endothelin A (ET ) receptor antagonism alone and in combination on endothelial vasomotor dysfunction in chronic heart failure (CHF) was compared. Vasoreactivity and superoxide anion formation were determined in aortic rings from Wistar rats with experimental CHF 12 weeks after extensive myocardial infarction compared with sham-operated animals. Rats were treated with placebo, with the ET receptor antagonist LU 135252 (30 mg/kg/d), with the ACE inhibitor trandolapril (0.3 mg/kg/d), or with a combination of LU 135252 and trandolapril. Infarct size was similar among the groups. In the placebo group, the concentration-response curve of the endothelium-dependent, acetylcholine-induced relaxation was significantly shifted to the right and the maximum relaxation was attenuated (R 53 +/- 3%) compared with the sham placebo group (R 72 +/- 3%). Treatment with LU 135252 as well as trandolapril significantly improved acetylcholine-induced maximum relaxation (LU 135252 66 +/- 4%, trandolapril 67 +/- 4%, p < 0.05 versus CHF placebo). In addition to R (LU 135252/trandolapril 70 +/- 4%), combination therapy also improved the pathologic rightward shift (p < 0.05). Increased O production in CHF was significantly reduced in all treatment groups. The increased relaxation elicited by exogenous superoxide dismutase in CHF was reduced to normal values by monotherapy and further attenuated by combination treatment. Although monotherapy with the ACE inhibitor trandolapril and the ET receptor antagonist LU 135252 improved endothelial dysfunction in experimental CHF, combination therapy was more effective.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2004

Raynaud's phenomenon and endothelial dysfunction in end-stage renal disease patients treated with hemodialysis.

BACKGROUND/AIMS: Steal syndrome is a well-known complication of arteriovenous shunt placement. Increased frequency of Raynaud's phenomenon (RP) especially concerning shunt limb is reported among hemodialysis (HD) patients. The aim of the study was to assess the relation of impairment of peripheral circulation diagnosed with cold stress test (CST) and thermography to the AV shunt location and markers of endothelial dysfunction in HD patients. METHODS: The study group comprised 21 patients (6 male, 15 female, mean age 32.6 +/- 15.0 years) treated with HD for a mean of 69 +/- 54 months. 10 healthy individuals (4 male, 6 female, mean age 38.6 +/- 14.7 years) served as controls. The diagnosis of RP was made upon the results of thermographic measurements during CST. Von Willebrand factor activity and antigen, endothelin-1 and plasma total homocysteine (tHcy) were measured in all subjects. RESULTS: RP was found significantly more often in HD patients than in controls: 11/21 vs. 1/10 (p = 0.04). RP occurred in both hands in 7/11 (64%) patients. tHcy was higher in HD patients than in the controls (31.7 +/- 13.9 vs. 10.9 +/- 3.2 microg/l, p < 0.0001). tHcy and von Willebrand factor antigen were significantly higher in the RP-positive than RP-negative patients or controls. CONCLUSION: Small vessel dysfunction diagnosed as positive RP is a frequent finding in HD patients. It seems that endothelial injury rather than AV shunt steal syndrome is responsible for development of RP in HD patients.

Adolescent↗
PubMed2004

Abnormal capillary permeability and endothelial dysfunction in hypertension with comorbid Metabolic Syndrome.

PURPOSE: Metabolic Syndrome as defined by ATP III criteria, a constellation of risk factors associated with insulin resistance, predisposes to premature atherosclerosis and early coronary events. Whether that negative risk profile is associated with endothelial dysfunction remains to be established. MATERIALS AND METHODS: Transcapillary escape rate of albumin (TERalb), a measure of capillary permeability and integrity of systemic capillary endothelium, and forearm vasodilation to intra-arterial acetylcholine (ACH), an index of nitric oxide (NO)-mediated vasomotor dysfunction, were assessed in 24 non-diabetic, uncomplicated hypertensive men with Metabolic Syndrome according to ATP III criteria (hypertension with at least two additional traits such as high triglycerides, low HDL, abdominal obesity, impaired fasting or post-load plasma glucose). Twelve age-matched lean normal hypertensive patients with normal lipid and glucose profile and nine normotensive subjects were the controls. All patients underwent lipids determination and fasting and post-OGTT insulin assessment; HOMA-IR was the index of insulin resistance. RESULTS: TERalb was higher in hypertensive patients with Metabolic Syndrome, without differences between hypertensive and normotensive controls. Blood pressure (BP), lipids, plasma glucose, insulin levels and HOMA-IR were unrelated to TERalb. Responses to acetylcholine were selectively attenuated in metabolic patients and, on an individual basis, related only to HDL cholesterol levels, independent of LDL cholesterol, BP, body size, triglycerides, and HOMA-IR values. No relationship existed between responses to acetylcholine and TERalb. CONCLUSIONS: Altered systemic capillary permeability characterizes insulin-resistant hypertensive patients with Metabolic Syndrome. That defect, which may promote early atherosclerosis development, coexists with blunted endothelial-mediated vasodilation, indicating a pervasive abnormality of endothelial function.

Acetylcholine↗
PubMed2003

Endothelial dysfunction in peripheral arterial disease is related to increase in plasma markers of inflammation and severity of peripheral circulatory impairment but not to classic risk factors and atherosclerotic burden.

OBJECTIVE: We undertook this study to evaluate in patients with peripheral arterial disease (PAD) the relationship of endothelial dysfunction, which is directly related to progression and clinical complications of atherosclerosis, with variables including classic risk factors, inflammation, severity of peripheral circulatory impairment, and atherosclerotic burden. METHODS: This cross-sectional study included outpatients seen in an academic angiologic unit. Eighty-eight consecutive patients with PAD (ankle/brachial index [ABI] < 0.90) were studied. The control group consisted of 30 age-matched and sex-matched healthy subjects. Main outcome measures were endothelial function in the form of brachial artery flow-mediated dilation (FMD), plasma levels of C-reactive protein (CRP) and fibrinogen, severity of PAD according to ABI, and atherosclerotic burden, ie, atherosclerosis in one leg or in two or more other sites. RESULTS: Compared with patients with FMD greater than 6.2% (ie, 5th percentile of FMD in control subjects), patients with FMD less than 6.2% had a similar prevalence of classic risk factors but higher median levels of CRP (1.6 vs 6.0 mg/L; P <.01) and fibrinogen (200 vs 374 mg/dL; P <.01). The two inflammatory markers were negatively correlated with FMD (P <.01). ABI was higher in patients with FMD greater than 6.2% than in those with worse endothelial function (0.72 +/- 0.15 vs 0.62 +/- 16; P <.01); there was no difference with respect to atherosclerotic burden. Multivariate analysis showed that the association of CRP, fibrinogen, and ABI with FMD less than 6.2% was unrelated to classic risk factors. In a second model, which included CRP, fibrinogen, and ABI, all three variables were independently related to FMD less than 6.2%. CONCLUSION: Inflammation and severity of circulatory impairment are implicated in the pathophysiology of dysfunctional endothelium in PAD.

Aged↗