European Journal of Vascular & Endovascular Surgery
Volume 34, Issue 6 , Pages 639-645, December 2007

Smooth Muscle Dysfunction in Patients Older than 54 Years of Age with Objective Evidence of Arteriosclerosis

Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku Sendai, Sendai 980-8574, Japan

Accepted 8 July 2007. published online 28 August 2007.

Article Outline

Objective

This investigation was designed to assess the relationship between flow-mediated vasodilatation (FMD) and nitroglycerin (NTG)-mediated vasodilatation (NMD) with atherosclerotic risk factors.

Methods

FMD and NMD were measured in 75 subjects including 57 patients with atherosclerotic disease (AAA/PAOD=30/27, age 72±7 years) and 18 controls. Brachial response to hyperemia and NTG were measured every minute after cuff deflation and NTG administration.

Results

In the 75 subjects, responses to NTG showed a sigmoid curve. Only 2 cases reached maximal diameter within 4 minutes after NTG, and 90% of the cases reached maximal diameter at 6 minutes or later (7.5±2.0 minutes). In patients with atherosclerotic disease, a multiple regression analysis showed higher FMD was associated with higher NMD, and higher NMD was associated with smaller vessel size, lower systolic blood pressure, higher FMD, lower carotid maximal IMT, lower serum levels of insulin, and lower HOMA-IR.

Conclusions

In subjects older than 54, NMD measured at 3 or 4 minutes after NTG administration would underestimate the NTG-dependent vasodilatation. NMD measured with the maximal responded diameter was associated with atherosclerotic risk factors, and it is therefore considered to be an important parameter in patients with atherosclerotic disease.

Keywords: FMD, NMD, Endothelial function, Smooth muscle function

 

Back to Article Outline

Introduction 

Both the smooth muscle and endothelium play a pivotal role in atherosclerosis.1, 2 Endothelial dysfunction is considered to be an early event in atherosclerosis, preceding ultrasonic evidence of atherosclerotic plaque.3 Numerous studies have documented impaired brachial ultrasound assessment of endothelium–dependent vasodilatation in the plaque-free peripheral arteries of asymptomatic children and adults at risk for atherosclerosis.4, 5, 6 This ultrasound study includes an assessment of the vasodilatory response to nitroglycerin (NTG), which acts directly at the level of the arterial smooth muscle and produces an endothelium-independent vasodilatation. Nitroglycerin-mediated dilatation (NMD) has been used to check the vasodilatory responsiveness of smooth muscle, but the smooth muscle function in itself has almost never been previously discussed. A few studies have recently demonstrated impaired NMD to be associated with a higher systolic blood pressure,7 the presence of diabetes mellitus,8 higher oxidized LDL, greater carotid IMT and familial hypercholesterolemia.9

There have been few studies of NMD and FMD in patients with peripheral arterial occlusive disease (PAOD) and abdominal aortic aneurysm (AAA).10, 11, 12, 13, 14

We examined not only the magnitude but also the time courses of the response to hyperemia and sublingual NTG.

Back to Article Outline

Methods 

Subjects 

We studied 57 patients with atherosclerotic disease (AD) including 30 patients with AAA and 27 with PAOD. The patients with PAOD had symptoms and all patients came to our hospital for the purpose of receiving appropriate treatment. AAA was diagnosed when a localized dilation of the abdominal aorta of at least 50% or larger than an adjacent normal portion was detected by either ultrasonography or computed tomography (CT). PAOD was diagnosed by duplex scanning or CT based on an ABI<0.90. No female subjects were included in this study, because sexual differences may confound the data analysis. The exclusion criteria were decompensated heart failure, malignant neoplasma, glaucoma, the need to receive insulin therapy, ischemic gangrene, and evidence of hepatic, renal or inflammatory disease.

The sex-matched 18 control adults included in the study had an ABI>0.9, normal electrocardiogram, and normal ultrasonographic findings of the abdominal aorta to iliac artery.

Our institutional ethics committee approved the study, and all participants gave their written informed consent.

Data collection 

All subjects were asked in detail regarding their medical history, particularly regarding cardiovascular risk factors, and any vascular events. After an overnight fast a venous sample was taken, the plasma was separated from the blood cells by centrifugation. The fasting blood sugar (FBS) was measured enzymatically (SRL, Tokyo, Japan). The serum insulin levels were determined by a 2-step enzyme immunoassay (SRL, Tokyo, Japan). The plasma total homocysteine was analyzed by high-pressure liquid chromatography (SRL, Tokyo, Japan). Plasma asymmetric dimethylarginine (ADMA) was determined using high-pressure liquid chromatography (SRL, Tokyo, Japan). The serum concentration of advanced glycation end products (AGEs) was measured with an enzyme-linked immunosorbent assay (SRL, Tokyo, Japan). The serum adiponectin level was determined by an enzyme-linked immunosorbent assay (SRL, Tokyo, Japan). The serum CRP was measured with a highly sensitive (hs) assay (Dade Bhering Diagnostics, Marburg, Germany). The serum triglyceride, and total cholesterol, HDL cholesterol, and LDL cholesterol levels were all measured with commercially available kits. A homeostasis model assessment of insulin resistance (HOMA-IR) was calculated using the following formula: fasting plasma insulin (μU/ml)×fasting glucose (mmol/L)/22.5. As previously reported,15 HOMA-IR was validated in diabetic subjects treated with diet therapy alone and in those treated with sulfonylureas. Atherosclerotic patients were studied by Carotid ultrasound by 2 independent sonographers blinded to the subject's clinical details. In brief, bilateral longitudinal scanning was performed from the common carotid artery to the internal carotid artery. The scan was focused on the posterior (far) wall, and performed in the optimal position. The maximal thickness of intima-media complex (maxIMT) was recorded and measured with electronic calipers.

Brachial ultrasound 

After an overnight (14 hours) fast, changes in the brachial diameter as a response to reactive hyperemia and as a response to 300μg of sublingual NTG was measured using ultrasound (Aplio SSA-700A 5–12-MHz linear array transducer, Toshiba) as previously described.16 Vasoactive medications, such as calcium antagonists, and β-blockers, ACE-inhibitors, ARBs, and Nitrates were not administered for at least 14 hours. Caffeinated beverages and smoking were not allowed on the day of the study. Briefly, the brachial artery was scanned in longitudinal sections 2 to 10cm above the elbow (control scan) after 15min of rest in the supine position. The depth and gain settings were optimized to identify the anterior and posterior intimal interfaces between the lumen and vessel wall, and a baseline scan was recorded on super-VHS for an offline analysis. Hyperemia was induced by inflating and deflating a forearm blood pressure cuff and it was inflated to 50mmHg above the systolic blood pressure for 5 minutes. The vasodilator response to hyperemia was recorded for 5 minutes after deflation. After at least 10 minutes rest, a further control scan was recorded. A single 300-μg dose of NTG was sublingually administered. After the administration, we poured some water over the tablet and looked into the mouth to see if the tablet was dissolving because in older patients dissolution may sometimes be delayed due to dentures or dryness of the mouth.17 Thereafter, the vasodilator response to NTG was recorded for 15 minutes. NTG was omitted if the subjects either refused it, had a systolic blood pressure of <100mm Hg, or a previous adverse reaction to nitrates.

Measurements were taken at end-diastole, coincident with the R-wave on ECG, every one minute after deflation or after the administration of NTG. The arterial diameter was analyzed for three cardiac cycles, and then these measurements were averaged. The diameter responded to reactive hyperemia and NTG was expressed as a percent change relative to the diameter immediately before cuff inflation and relative to the diameter immediately before drug administration, respectively. The same operator, who was blinded to the details of subjects' data, studied all brachial ultrasound images. In our laboratory, the intraobserver variability for repeated measurements of resting arterial diameter was 0.02±0.01mm, for FMD was 0.49±0.27 (%), and for NMD was 0.44±0.34 (%), respectively.

Brachial IMT was measured as previously described.9 The same segment of the brachial artery for the analysis of vasodilator response was measured for brachial IMT. The scan was focused on the posterior wall, and 8 measurements were taken at end-diastole, coincident with the R-wave, at even intervals. The average of these measurements was used as the mean brachial IMT in the analysis.

Statistical analysis 

All descriptive data were expressed as the mean±SD. A comparison for continuous variables between the groups was made by either an Analysis of covariance (ANCOVA), the t-test or the Mann-Whitney test. Categorial variables were compared with either the χ2 test or Fisher's exact probability test. Univariate associations between the study variables were analyzed by calculating the Pearson's correlation coefficient. A multiple stepwise regression analysis was used to assess which variables were significantly related to FMD or NMD. In the regression models, we first assessed the presence of a univariate correlation between the variables and FMD or NMD. The variables were then entered into the model based on the selection criteria of P<0.10. A P value of less than 0.05 was considered to be significant. All statistical analyses were performed using the Stat View 5.0 statistical analysis software program.

Back to Article Outline

Results 

All 75 subjects underwent the FMD evaluation, but 2 AD patients refused to take NTG. In the present study, the AD patients were significantly older than control subjects (72±7 years, range 54 to 86 versus 69±3 years, range 65 to 75, p=0.013). Therefore, a comparison of continuous variables between two groups was made by ANCOVA while adjusting for age. In comparison to the control subjects, the AD patients had a lower FMD (2.1±1.7 versus 3.3±2.3%, p=0.014) but a similar NMD (17.9±7.2 versus 18.1±6.6%, p=0.918). The NMD measured at 3 minutes after administration (NMD3) was lower in the AD patients but the difference was not statistically significant (7.6±5.2 versus 10.4±6.8%, p=0.070). The characteristics of the subjects are shown in Table 1, Table 2.

Table 1.
Control (N=18)Patients (N=57)
Age (y)69±372±7*
Sex (M/F)18/057/0
Body mass index (kg/m2)24.8±2.223.3±3.1
Coronary artery disease0 (0)16 (28)*
Cerebrovascular disease0 (0)7 (12)
Hypertension3 (17)46 (80)*
Hyperlipidemia3 (17)20 (35)
Diabetes mellitus2 (11)13 (23)
IGT7 (34)16 (28)
Smoking (pack-year)1.9±4.852±28*

Treatment
ACE inhibitors020 (35)*
Calcium antagonists039 (68)*
ARBs015 (26)*
Nitrates012 (21)
Statins09 (16)
Cilostazol011 (19)
Ticlopidine hydrochloride05 (9)
Aspirin016 (28)*
Oralhypoglycemic agents05 (9)

The numbers in parentheses represent the percentages.

*P<.05 vs control subjects.

Table 2.
Control (N=18)Patients (N=57)
Systolic BP (mm Hg)128±17138±24
Diastolic BP (mm Hg)82±1081±11
Total cholesterol (mmol/L)4.92±0.805.07±0.88
LDL cholesterol (mmol/L)2.84±0.643.23±0.64*
HDL cholesterol (mmol/L)1.24±0.281.13±0.36
Triglycerides (mmol/L)1.15±0.621.37±0.75
hs-CRP (mg/L)1.16±1.482.78±3.48
ADMA (nmol/mL)0.47±0.050.47±0.09
Total homocysteine (nmol/mL)9.7±2.113±3.6*
AGEs (mU/ml)2.46±0.522.82±0.62*
Fasting blood sugar (mmol/L)5.10±0.526.04±1.27*
insulin (μU/mL)3.82±2.418.41±6.45*
HOMA-R0.88±0.602.24±1.80*
Adiponectin (μg/mL)9.74±5.8010.39±5.11
Brachial IMT (mm)0.41±0.080.46±0.06*
Brachial artery diameter (mm)4.5±0.64.3±0.7

*P<.05 vs control subjects.

In the AD group, FMD and NMD and NMD3 were similar between the patients with AAA and PAOD.

Time course of the brachial artery response in this study 

In the 57 AD patients, the response to hyperemia reached a maximal diameter at 1.3±0.6 minutes post-deflation (1 min – 42 cases, 2min – 13 cases, 3 min – 1 case, 4 min – 1case). While in the control subjects the response to hyperemia reached a maximal diameter at at 1.1±0.2 minutes (1 min – 17 cases, 2 min – 1 case). The time courses of response to NTG are shown in Fig. 1, Fig. 2. In the AD patients and control subjects the brachial artery reached a maximal diameter at 7.6±2.2 (range 4 to 13) and 7.1±0.9 (range 5 to 8) minutes post-NTG administration, respectively. The time courses showed a sigmoid curve, a gradual increase from 0 to 2 minutes and a rapid increase from 2 to about 5 minutes, followed again by a gradual increase. In the 73 cases, only two cases (2.7%) reached a maximal diameter at 4 minutes post-NTG administration, while 66 cases (90.4%) did so at 6 minutes or later.

  • View full-size image.
  • Fig. 1 

    The time courses of the brachial artery response to NTG in patients with atherosclerotic disease. The time courses showed a sigmoid curve. Only 2 patients reached maximal diameter within 4 minutes after administration. The figure shows the curves for only 55 cases because 2 cases refused to take the NTG tablets.

  • View full-size image.
  • Fig. 2 

    The time courses of the brachial artery response to NTG in control subjects. Control subjects also showed a sigmoid curve. The figure shows the curves of 16 cases because we failed to identify both of intimal interfaces at one to two points of measurements in 2 cases (Case 1 failed to identify NMD2 and NMD4. Case 2 failed NMD2).

FMD and atherosclerotic risk factors in patients with atherosclerotic disease 

According to a univariate analysis, the FMD in the 57 patients was inversely correlated with the vessel size, SBP, HOMA-IR, and it was directly and closely correlated with the maximal NMD (Fig. 3). In a multiple stepwise regression analysis, the serum levels of insulin and brachial IMT (p<0.1) were included in the model in addition to the above 4 parameters, and either insulin or HOMA-IR was separately included in the model because insulin correlated very closely with HOMA-IR (r=0.979, p<0.001). The independent determinant of FMD was the NMD. No other parameter was independently associated with FMD (Table 3). The squared multiple correlation coefficient adjusted for the degree of freedom (R2) was 0.447 when HOMA-IR was included in the model, and 0.375 when serum levels of insulin was included.

  • View full-size image.
  • Fig. 3 

    Correlation between the flow-mediated vasodilatation (FMD) and the NTG-mediated vasodilatation (NMD) in patients with atherosclerotic disease. FMD was directly and closely correlated with NMD (n=55).

Table 3.
UnivariateMultivariate
rpβp
FMD
NMD0.630<0.0010.676 (0.622)<0.001 (<0.001)
vessel size−0.445<0.001–0.803 (0.351)
brachial IMT−0.2290.090–0.522 (0.388)
HOMA-R−0.2640.049–0.422
insulin−0.2430.068–(0.450)
SBP−0.3640.005–0.543 (0.464)

NMD
vessel size−0.551<0.001−0.443 (−0.415)<0.001 (<0.001)
SBP−0.468<0.001−0.418 (−0.465)<0.001 (<0.001)
FMD0.630<0.0010.316 (0.241)<0.001 (0.016)
maxIMT−0.2490.084−0.210 (−0.269)0.007 (0.001)
HOMA-R−0.2920.032−0.1940.027
insulin−0.2710.044(−0.236)(0.012)
Smoking status−0.2680.049–0.305 (0.258)
Total cholesterol−0.2830.041–0.311 (0.388)
brachial IMT−0.2270.099–0.798 (0.650)

The numbers in parentheses indicate standard regression coefficient and p value when insulin was included in the model.

NMD and atherosclerotic risk factors in patients with atherosclerotic disease 

According to a univariate analysis, the NMD in the 55 patients was inversely correlated with the vessel size, smoking status, SBP, total cholesterol, serum levels of insulin, HOMA-IR, and it was also directly correlated with FMD. A multiple stepwise regression analysis included the brachial IMT (p<0.1) and carotid maxIMT (p<0.1). In a multivariate model, FMD, SBP, vessel size, carotid maxIMT, serum levels of insulin and HOMA-IR were independently associated with NMD (Table 3). R2 was 0.754 when HOMA-IR was included in the model and 0.714 when insulin was included.

NMD3 was associated with FMD and the vessel size, though, no other association was demonstrated between NMD3 and risk factors.

Similar results were obtained when patients using hypoglycemic agents were excluded.

Back to Article Outline

Discussion 

The present study demonstrated a close correlation between FMD, the endothelium-dependent vasodilatory response, and NMD, the smooth muscle-dependent response, in patients with atherosclerotic disease. The only independent determinant of FMD was NMD on a multiple stepwise regression analysis. Independent determinants of impaired maximal NMD included a larger vessel size, higher SBP, lower FMD, increased carotid maxIMT, increased serum levels of insulin, and higher HOMA-IR. We are aware of no published reports that have described the associations between smooth muscle-dependent vasodilatation and risk factors in patients with atherosclerotic disease. Most of the studies measuring the vasodilator response induced by a single high dose of NTG at 3–4 minutes did not show any association with risk factors. We measured the vasodilator response every minute after administration, although previous reports recommended subplateau doses of NTG.9, 18 Using this method, we detected the maximal diameter induced by a single dose of NTG. It is generally thought that NTG has a plasma half-life of 3 minutes and peak plasma concentrations occurs at 4 to 5 minutes.19 As a result, most observers recommend measurements at 3 to 4 minutes after administration.16 In the present study, the time courses of the vasodilatory response to NTG showed a sigmoid curve, and 90% of the subjects showed a maximal diameter after 6 minutes or later. The reason for this discrepancy was not because of dentures or of dryness of the mouth, but because pharmacodynamic or pharmacokinetic changes of NTG tend to be delayed in elderly subjects.19 Alternatively, hypertension, insulin resistance or some other risk factors unidentified in this study may also have delayed NMD. Therefore, at least in subjects older than 54 years of age, measuring the diameter at 3 or 4 minutes post-NTG may underestimate the smooth muscle function, and observers should therefore take measurements at least 6 minutes or later when performing one point measurements.

In theory the brachial ultrasound test for endothelial function is a method measuring the relaxing effect of the smooth muscle induced by endothelium-derived endogenous nitric oxide (NO). For that reason, FMD should be considered a parameter including function of the endothelium and of smooth muscle and it would be important to evaluate smooth muscle function.

A question remains regarding whether an impaired dilator response to NTG might be due to mechanical forces limiting the artery's ability to relax or due to a decreased use of NTG inside the smooth muscle. To explain whether mechanical forces limited the vasodilatory response or not, we measured the brachial IMT, although we performed brachial ultrasound in an artery without any plaques. The brachial IMT did not significantly correlate with NMD, nor was any association observed based on a multiple regression analysis. Hence, the likely explanation for our finding is a decreased use of NTG inside the smooth muscle, i.e. smooth muscle dysfunction.

Our data demonstrated a higher FMD, a higher SBP, higher serum levels of insulin, and a higher HOMA-IR to be independently associated with an impaired NMD. The reason why FMD was involved in NMD was not because endothelial function affected NTG mediated vasodilatation. NTG causes a slight increase in the brachial flow20 but such a low stimulus would not evoke NO production in patients with seriously attenuated endothelial function. The mechanisms responsible for smooth muscle dysfunction remain speculative. Various mechanisms may be involved in the vascular dysfunction in complicated patients. Our speculation is that a decrease in the bioactivation of NTG by enzymes such as mtALDH (described by Chen et al.21) may be a possible mechanism in the development of smooth muscle dysfunction. Measuring the vasodilatory response to sodium nitroprusside, a direct stimulator of soluble guanylate cyclase, may thus help to explain whether an attenuated bioactivation of NTG is present or not.

Recently, some observers have indicated the predictive value of FMD for cardiovascular events in PAOD.22, 23 Although NMD was not an independent predictor of event in those reports, this does not mean that NMD had no association with the clinical outcome because NMD was measured at 3 minutes after NTG administration. NMD was therefore likely underestimated.

Our study has some limitations. First, although it remains controversial regarding whether atherosclerosis is a causative factor in aneurysms,24 we included patients with AAA in the atherosclerotic disease group because most patients with AAA exhibit risk factors for atherosclerosis, manifestations of coronary or cerebrovascular disease1, 25 and ultrasonographic evaluation of FMD, NMD, NMD3 were similar between AAA and PAOD. Second, our sample size was limited and additional large-scale experimental studies are needed to explain the causal relationships between risk factors and an impaired vascular function. Third, although medication was discontinued for at least 14 hours before study, we cannot rule out the possibility that the long-acting effect of drugs may have beneficially influenced the FMD and NMD in the AD patients. However, long-term drug discontinuation is difficult both therapeutically and ethically.

In conclusion, in patients with AAA and PAOD, the vasodilatory response to exogenous NO was associated with FMD, SBP, the serum levels of insulin, HOMA-IR and carotid maxIMT. FMD was only associated with NMD. Regarding the value of an ultrasound test for patients with objective evidence of atherosclerotic disease, not only FMD but also NMD may be an important marker. A large-scale study evaluating the association between NMD measured with a maximal responded diameter and clinical outcome is thus called for.

Back to Article Outline

Acknowledgments 

The authors thank Yoichi Yoshida for helping to study the control subjects and Brian Quinn for revising the paper.

Back to Article Outline

References 

  1. Faxon DP, Fuster V, Libby P, Beckman JA, Hiatt WR, Thompson RW, et al. Atherosclerotic Vascular Disease Conference: Writing Group III: pathophysiology. Circulation. 2004;109(21):2617–2625
  2. Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med. 1999;340(2):115–126
  3. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109(23 Suppl. 1):III27–III32
  4. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340(8828):1111–1115
  5. Thorne S, Mullen MJ, Clarkson P, Donald AE, Deanfield JE. Early endothelial dysfunction in adults at risk from atherosclerosis: different responses to L-arginine. J Am Coll Cardiol. 1998;32(1):110–116
  6. Balletshofer BM, Rittig K, Stock J, Lehn-Stefan A, Overkamp D, Dietz K, et al. Insulin resistant young subjects at risk of accelerated atherosclerosis exhibit a marked reduction in peripheral endothelial function early in life but not differences in intima-media thickness. Atherosclerosis. 2003;171(2):303–309
  7. Gokce N, Holbrook M, Duffy SJ, Demissie S, Cupples LA, Biegelsen E, et al. Effects of race and hypertension on flow-mediated and nitroglycerin-mediated dilation of the brachial artery. Hypertension. 2001;38(6):1349–1354
  8. Adams MR, Robinson J, McCredie R, Seale JP, Sorensen KE, Deanfield JE, et al. Smooth muscle dysfunction occurs independently of impaired endothelium-dependent dilation in adults at risk of atherosclerosis. J Am Coll Cardiol. 1998;32(1):123–127
  9. Jarvisalo MJ, Lehtimaki T, Raitakari OT. Determinants of arterial nitrate-mediated dilatation in children: role of oxidized low-density lipoprotein, endothelial function, and carotid intima-media thickness. Circulation. 2004;109(23):2885–2889
  10. Knipp BS, Peterson DA, Rajagopalan S, Kehrer C, Ford JW, D'Alecy LG, et al. Impaired vasoreactivity despite an increase in plasma nitrite in patients with abdominal aortic aneurysms. J Vasc Surg. 2002;35(2):363–367
  11. Brevetti G, Silvestro A, Di Giacomo S, Bucur R, Di Donato A, Schiano V, et al. 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. J Vasc Surg. 2003;38(2):374–379
  12. Yataco AR, Corretti MC, Gardner AW, Womack CJ, Katzel LI. Endothelial reactivity and cardiac risk factors in older patients with peripheral arterial disease. Am J Cardiol. 1999;83(5):754–758
  13. Muluk SC, Muluk VS, Kelley ME, Whittle JC, Tierney JA, Webster MW, et al. Outcome events in patients with claudication: a 15-year study in 2777 patients. J Vasc Surg. 2001;33(2):251–257[discussion 257–258]
  14. Koskas F, Kieffer E. Long-term survival after elective repair of infrarenal abdominal aortic aneurysm: results of a prospective multicentric study. Association for Academic Research in Vascular Surgery (AURC). Ann Vasc Surg. 1997;11(5):473–481
  15. Emoto M, Nishizawa Y, Maekawa K, Hiura Y, Kanda H, Kawagishi T, et al. Homeostasis model assessment as a clinical index of insulin resistance in type 2 diabetic patients treated with sulfonylureas. Diabetes Care. 1999;22(5):818–822
  16. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, et al. Guidelines 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(2):257–265
  17. Ducharme A, Dupuis J, McNicoll S, Harel F, Tardif JC. Comparison of nitroglycerin lingual spray and sublingual tablet on time of onset and duration of brachial artery vasodilation in normal subjects. Am J Cardiol. 1999;84(8):952–954A8
  18. Raitakari OT, Seale JP, Celermajer DS. Impaired vascular responses to nitroglycerin in subjects with coronary atherosclerosis. Am J Cardiol. 2001;87(2):217–219A8
  19. Hashimoto S, Kobayashi A. Clinical pharmacokinetics and pharmacodynamics of glyceryl trinitrate and its metabolites. Clin Pharmacokinet. 2003;42(3):205–221
  20. Wu HD, Katz SD, Beniaminovitz A, Khan T, DiTullio MR, Homma S. Assessment of endothelium-mediated vasodilation of the peripheral circulation by transcutaneous ultrasonography and venous occlusion plethysmography. Heart Vessels. 1999;14(3):143–148
  21. Chen Z, Zhang J, Stamler JS. Identification of the enzymatic mechanism of nitroglycerin bioactivation. Proc Natl Acad Sci U S A. 2002;99(12):8306–8311
  22. Gokce N, Keaney JF, Hunter LM, Watkins MT, Nedeljkovic ZS, Menzoian JO, et al. Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. J Am Coll Cardiol. 2003;41(10):1769–1775
  23. Brevetti G, Silvestro A, Schiano V, Chiariello M. Endothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: additive value of flow-mediated dilation to ankle-brachial pressure index. Circulation. 2003;108(17):2093–2098
  24. Thompson RW, Geraghty PJ, Lee JK. Abdominal aortic aneurysms: basic mechanisms and clinical implications. Curr Probl Surg. 2002;39(2):110–230
  25. Sukhija R, Aronow WS, Yalamanchili K, Sinha N, Babu S. Prevalence of coronary artery disease, lower extremity peripheral arterial disease, and cerebrovascular disease in 110 men with an abdominal aortic aneurysm. Am J Cardiol. 2004;94(10):1358–1359

PII: S1078-5884(07)00428-5

doi:10.1016/j.ejvs.2007.07.001

European Journal of Vascular & Endovascular Surgery
Volume 34, Issue 6 , Pages 639-645, December 2007

Article Tools

* Image Usage & Resolution