Brachial-Ankle Pulse Wave Velocity Is Useful for Evaluation of Complications in Type 2 Diabetic Patients

807 Original Article Brachial-Ankle Pulse Wave Velocity Is Useful for Evaluation of Complications in Type 2 Diabetic Patients Katsumi ASO, Masaaki MIYATA, Tadahiro KUBO, Hiroshi HASHIGUCHI, Michiyo FUKUDOME, Eriko FUKUSHIGE, Nobuyuki KORIYAMA, Mitsuhiro NAKAZAKI, Shinichi MINAGOE, and Chuwa TEI Pulse wave velocity (PWV) is useful for the evaluation of aortic stiffness. The brachial-ankle PWV (bapwv) and carotid PWV (from heart to carotid) were compared to study the relation of these two types of PWVs to diabetic complications in patients with type 2 diabetes mellitus. The bapwv was determined by oscillometrically measuring the pulse volume record at the upper arm and ankles. The carotid PWV was measured tonometrically. Ninety patients with type 2 diabetes mellitus were divided into tertile groups on the basis of bapwv or carotid PWV. The correlations of these variables with albuminuria, peripheral neuropathy, coefficient of variation of R-R intervals (CV R-R) on the electrocardiogram at rest, and retinopathy were examined by logistic regression analysis. After adjustment for age, systolic blood pressure, and duration of diabetes, logistic regression analysis showed that bapwv was directly related to the frequencies of albuminuria, decreased CV R-R, peripheral neuropathy, and retinopathy. In contrast, carotid PWV did not significantly correlate with any diabetic complications. We conclude that oscillometrically determined bapwv is related to the risk of diabetic microvascular disease in patients with type 2 diabetes mellitus and suggested to be useful for assessing risk factors of diabetic complications. (Hypertens Res 2003; 26: 807 813) Key Words: pulse wave velocity, type 2 diabetes mellitus, neuropathy, retinopathy, albuminuria Introduction Pulse wave velocity (PWV) has been used as a noninvasive clinical index of aortic stiffness. Increased PWVs are found in various diseases associated with atherosclerosis, including diabetes mellitus (1), hypertension (2), dyslipidemia (3), and severe renal disease (4). Aortic PWV (carotid to femoral PWV), calculated on the basis of the transmission time and distance between the carotid artery and femoral artery, is the most widely used type of PWV. Conventionally, PWV has been measured tonometrically. Although tonometry is noninvasive, it requires that the transducer be carefully adjusted to obtain an accurate pulse wave. Such sophisticated and complex techniques are inconvenient for routine clinical examinations. Hasegawa et al. reported that heart to carotid PWV (carotid PWV) is easier to determine than aortic PWV and may be useful in evaluating risk factors for atherosclerosis and the response to therapeutic intervention in hypertensive patients (5). Woolam et al. found that carotid to radial PWV is increased in diabetic patients (1). Previous studies have thus shown that PWVs other than carotid to femoral are also clinically useful. Recently, a device has been developed that can determine brachial-ankle PWV (bapwv) by oscillometrically measuring the pulse volume record at the upper arm and the ankles. We reported that bapwv correlates with age in healthy sub- From the First Department of Internal Medicine, Faculty of Medicine, Kagoshima University, Kagoshima, Japan. Address for Reprints: Chuwa Tei, M.D., First Department of Internal Medicine, Faculty of Medicine, Kagoshima University, 8 35 1 Sakuragaoka, Kagoshima 890 8520, Japan. E-mail: tei@m.kufm.kagoshima-u.ac.jp Received March 3, 2003; Accepted in revised form July 10, 2003.

808 Hypertens Res Vol. 26, No. 10 (2003) jects, suggesting that it reflects age-related changes in vascular stiffness (6). To our knowledge, no study has compared the usefulness of bapwv with that of aortic PWV for the evaluation of diabetic complications. Because bapwv is derived from pulse waves at the upper arm and ankles, it may better reflect the characteristics of peripheral PWV than aortic PWV. Therefore, the clinical significance of bapwv may differ from that of aortic PWV. In this study, we measured bapwv and carotid PWV in patients with type 2 diabetes mellitus to examine the relation of these two types of PWV to the duration of diabetes and the presence of diabetic complications. Methods Subjects and Clinical Characteristics The protocol for this study was approved by the institutional review board of Kagoshima University. Informed consent was obtained from all patients before enrollment. The study group comprised 90 patients with type 2 diabetes mellitus (43 men and 47 women; 22 to 84 years old) who were receiving treatment on an outpatient basis at Kagoshima University Hospital. Type 2 diabetes mellitus was diagnosed according to the criteria recommended by the American Diabetes Association (7). Twenty patients were receiving insulin therapy, 53 oral antidiabetic agents, and 17 diet therapy alone. Blood Pressure and Laboratory Data Blood pressures and ankle/brachial blood pressure index (ABI) were measured with the use of a Waveform Analyzer (BP-203RPE; Colin, Komaki, Japan). Hypertension was defined as the taking of antihypertensive agents, a systolic blood pressure (SBP) higher than 140 mmhg, or a diastolic blood pressure (DBP) higher than 90 mmhg (8). Among the 26 patients who were receiving antihypertensive agents, 8 received calcium channel blockers, 7 received angiotensin converting enzyme inhibitors, and 11 received both types of drugs. They did not take any medications, including antihypertensive or vasodilating drugs, on the morning of blood pressure and PWV measurements. There was no patient with arteriosclerosis obliterans (ASO) who showed an ABI of less than 0.9. After an overnight fast, blood was withdrawn for analysis of serum concentrations of glucose, C-peptide, HbA1c, total cholesterol, triglycerides, and high density lipoprotein (HDL) cholesterol by standard laboratory methods. Low density lipoprotein (LDL) cholesterol was estimated by the Friedewald equation. Patients were considered dyslipidemic if they were taking antihyperlipidemic agents or if the serum LDL cholesterol concentration was higher than 130 mg/dl or the serum HDL cholesterol concentration was lower than 35 mg/dl (lower than 45 mg/dl in women) (9). Information on the duration of diabetes was obtained by a self-administered questionnaire. Patients were asked to state the age at which they had been diagnosed with diabetes mellitus at the hospital, or when they had been informed of glucose intolerance at a health check-up. Diabetic Complications Nephropathy was evaluated on the basis of the degree of albuminuria. Urinary albumin excretion was measured by radioimmunoassay of urine samples obtained by random spot collection. The value was corrected by the urinary creatinine excretion. Albuminuria was classified into three groups according to the diagnostic recommendations of the American Diabetes Association: no albuminuria was defined as a urinary albumin level of less than 30 mg/g creatinine; microalbuminuria as a urinary albumin level of 30 to 300 mg/g creatinine; and macroalbuminuria as a urinary albumin level of more than 300 mg/g creatinine (10). After excluding 10 patients with distinct hematuria or suspected renal disease unrelated to diabetes and 3 with a serum creatinine concentration of more than 1.3 mg/dl, the remaining 77 patients were divided into 2 groups: 49 patients with no albuminuria (a urinary albumin level of less than 30 mg/g creatinine) and 28 with microalbuminuria (19 patients) or macroalbuminuria (9 patients). Diabetic peripheral neuropathy was evaluated with the use of Semmes-Weinstein monofilaments. To detect early diabetic peripheral neuropathy, a 4-g monofilament was used as recommended by Nagai et al. (11). Subjects were tested for their ability to sense the monofilament at three sites of the foot: the great toe, the plantar aspect of the first metatarsal, and the plantar aspect of the fifth metatarsal. The patients were divided into 2 groups: those able to feel the 4-g monofilament (normal group; 70 patients) and those unable to feel the 4-g monofilament (insensitive group; 20 patients). The coefficient of variation of R-R intervals (CV R-R) on the electrocardiogram was measured to quantitatively assess autonomic nerve function. A total of 8 patients who were receiving digitalis or other drugs that affect sinus rhythm, who had atrial fibrillation or sick sinus syndrome, or who had frequent ventricular or supraventricular extrasystoles were excluded from analysis of CV R-R. In the remaining 82 patients, CV R-R was analyzed as described by Sasaki et al., with a value of 2% or less defined as decreased CV R-R (12). CV R-R was normal in 50 patients and decreased in 32. Retinopathy was diagnosed by experienced ophthalmologists, who divided the patients into those with retinopathy (54 patients) and those without retinopathy (36 patients). Diabetic retinopathy was present in a simple form in 23 patients, in a preproliferative form in 16, and in a proliferative form in 15.

Aso et al: Aortic Stiffness and Diabetic Complications 809 Table 1. Clinical Characteristics of Patients with Type 2 Diabetes Mellitus Measurement of PWV Total (n 90) Age (years) 60.3 11.9 Gender (male/female) 43/47 BMI (kg/m 2 ) 22.7 3.20 Duration (years) 13.7 7.50 Fasting plasma glucose (mg/dl) 151.3 51.60 Serum C-peptide (ng/ml) 1.89 0.99 HbA1c (%) 7.5 1.6 Total cholesterol (mg/dl) 197.1 32.00 Triglycerides (mg/dl) 106.9 67.40 HDL cholesterol (mg/dl) 57.4 16.2 LDL cholesterol (mg/dl) 117.3 25.60 Dyslipidemia ( / ) 42/48 SBP (mmhg) 128.6 16.60 DBP (mmhg) 75.8 9.50 Hypertension ( / ) 47/43 Smoking ( / ) 60/30 BMI, body mass index; HDL, high density lipoprotein; LDL, low density lipoprotein; SBP, systolic blood pressure; DBP, diastolic blood pressure. Data are the means SD. The bapwv was measured as reported previously (6, 13). The bapwv was automatically calculated with the use of a Colin Waveform Analyzer according to the following equation: bapwv (D1 D2)/T1, where D1 is the distance from the heart to the left ankle, and D2 is the distance from the heart to the right upper arm. These distances were calculated automatically on the basis of the subject s height. T1 is the time from the onset of the rise in the pulse volume record of the right upper arm to the onset of the rise in the pulse volume record of the left ankle. In addition to the procedures described above, a tonometry transducer was placed over the left carotid artery, and carotid PWV (heart to carotid), derived from elastic vessels, was measured. Carotid PWV was calculated by dividing the distance from the suprasternal notch to the transducer on the left side of the neck by the time from the second heart sound of the phonocardiogram to the notch of the carotid pulse wave (5). The subjects were divided into tertile groups on the basis of the bapwv or carotid PWV, and the relations of bapwv and carotid PWV to diabetic complications were studied. The bapwvs in the three groups were as follows: 1) 1,550 cm/s or less, 2) greater than 1,550 cm/s but not more than 1,900 cm/s, and 3) greater than 1,900 cm/s. Carotid PWVs were classified as follows: 1) 750 cm/s or less, 2) greater than 750 cm/s but not more than 900 cm/s, and 3) greater than 900 cm/s. Statistical Analysis Data are expressed as the means SD. Group comparison of parametric and nonparametric data was done by Student s t- test and Mann-Whitney U test, respectively. Differences in frequency were tested by χ 2 analysis. Relations between continuous variables were analyzed by linear regression analysis. To adjust for the effects of age, blood pressure, and duration of diabetes, logistic regression analysis was used to examine the relations between PWVs and diabetic complications. Carotid PWV and bapwv classifications, age, SBP, and duration of diabetes were defined as independent variables, and the presence or absence of diabetic complications was defined as the dependent variable. All statistical analyses were done with StatView, version 5.0 (Windows). P values less than 0.05 were considered to indicate statistical significance. Results The clinical characteristics of the patients are shown in Table 1. The frequency of hypertension was 48%, of dyslipidemia 54%, and of smoking 33%. Table 2 shows the comparison of bapwv, carotid PWV or mean blood pressure between patients with diabetic complications and those without diabetic complications. The bapwv and mean blood pressure in patients with diabetic complications were significantly higher than those in patients without complications. There was no significant difference in incidence of hypertension between patients with and without diabetic complications. In contrast, carotid PWV did not differ significantly between patients with diabetic complications and those without complications. The relations of bapwv and carotid PWV to age, blood pressure, and duration of diabetes are shown in Fig. 1. There were significant positive correlations of bapwv with age (r 0.58, p 0.0001) and SBP (r 0.61, p 0.0001) (Fig. 1A, C). Carotid PWV also positively correlated with age (r 0.53, p 0.0001) and SBP (r 0.39, p 0.0005) (Fig. 1B, D). The duration of diabetes positively correlated with bapwv (r 0.35, p 0.001), but did not correlate with carotid PWV (Fig. 1E, F). Table 3 shows the results of logistic regression analysis of the relations between bapwv and the frequency of diabetic complications after adjustment for the effects on bapwv of age, SBP, and duration of diabetes. The frequency of diabetic retinopathy and the odds ratio for this complication were significantly higher in the 1,900 cm/s group than in the 1,550 cm/s group. The frequencies of albuminuria, peripheral neuropathy, and decreased CV R-R were directly related to the bapwv, and the odds ratios for these complications increased significantly with increasing bapwvs. As shown in Fig. 2, single regression analysis revealed a significant negative correlation between bapwv and CV R-R (r 0.48, p 0.0001).

810 Hypertens Res Vol. 26, No. 10 (2003) Table 2. Comparison of bapwv, Carotid PWV, or Mean BP between Patients with ( ) and without ( ) Diabetic Complications bapwv (cm/s) Carotid PWV (cm/s) Mean BP (mmhg) Retinopathy ( ) 1,534.2 254.0 804.6 184.7 93.5 10.2 ( ) 1,840.3 352.6 874.3 204.9 99.2 12.1 Albuminuria ( ) 1,615.3 330.8 849.1 153.3 93.7 10.3 ( ) 1,853.7 347.9 808.2 153.3 100.2 12.0 0 Peripheral neuropathy ( ) 1,665.1 353.1 838.8 203.8 95.6 11.5 ( ) 1,902.4 270.7 872.9 183.4 101.6 11.4 0 CV R-R 2% ( ) 1,558.1 293.9 823.9 202.2 93.5 10.4 ( ) 1,950.0 298.0 897.0 198.3 102.1 11.3 0 bapwv, brachial-ankle pulse wave velocity; BP, blood pressure; CV R-R, coefficient of variation of R-R intervals. p 0.0001, p 0.001, p 0.01, p 0.05 compared to ( ). Fig. 1. Relation between age and bapwv (A: ) or carotid PWV (B: ) in patients with type 2 diabetes. Relation between SBP and bapwv (C: ) or carotid PWV (D: ). Relation between duration of diabetes and bapwv (E: ) or carotid PWV (F: ).

Aso et al: Aortic Stiffness and Diabetic Complications 811 Table 3. Relations between bapwv and Diabetic Complications as Analyzed by Multivariate Logistic Regression Analysis after Adjustment for Age, Systolic Blood Pressure, and Disease Duration bapwv (cm/s) N Retinopathy OR 95% CI p 1,550 33 10 1.0 1,550 1,900 31 21 3.8 [0.7, 19.9] 0.115 1,900 26 23 20.9 [2.7, 164.4] 0.004 bapwv (cm/s) N Albuminuria OR 95% CI p 1,550 30 4 1.0 1,550 1,900 24 12 6.4 [1.1, 36.9] 0.038 1900 23 12 7.6 [1.0, 55.4] 0.045 bapwv (cm/s) N Peripheral neuropathy OR 95% CI p 1,550 33 1 1.0 1,550 1,900 31 10 12.8 [1.1, 149.8] 0.042 1,900 26 9 15.2 [1.0, 221.3] 0.047 bapwv (cm/s) N CV R-R 2% OR 95% CI p 1,550 31 1 1.0 1,550 1,900 27 15 22.6 [2.1, 247.5] 0.011 1,900 24 16 29.4 [2.2, 385.4] 0.010 bapwv, brachial-ankle pulse wave velocity; CV R-R, coefficient of variation of R-R intervals; OR, odds ratio; 95% CI, 95% confidence interval. Table 4. Sensitivity, Specificity, and Accuracy for the Detection of Diabetic Complications Diabetic complications Sensitivity Specificity Accuracy (%) (%) (%) Retinopathy 68.5 75.0 71.1 Albuminuria 75.0 67.3 70.1 Peripheral neuropathy 75.0 55.7 60.0 CV R-R 2% 78.1 68.0 71.2 CV R-R, coefficient of variation of R-R intervals. Fig. 2. Relation between bapwv and CV R-R in patients with type 2 diabetes. Table 4 shows the sensitivity, specificity, and accuracy for the detection of diabetic complications with the cut off values, bapwv 1,700 cm/s, which yielded the maximal accuracy for the detection of diabetic complications. Logistic regression analysis showed no significant relation between carotid PWV and any diabetic complications. Serum concentrations of glucose, C-peptide, total cholesterol, triglycerides, HDL cholesterol, and HbA1c were unrelated to either carotid PWV or bapwv. Discussion We concurrently measured bapwv, derived principally from elastic and muscular vessels, and carotid PWV (heart to carotid), derived mainly from elastic vessels, and studied the relations of these variables to complications in diabetic patients. Elastic arteries are the largest artery type and have walls consisting chiefly of elastin; they include the aorta and the branches originating from its arch. Muscular arteries, such as the femoral and brachial artery, distribute blood to various parts of the body. The walls of these arteries consist chiefly of circularly disposed smooth muscle fibers which constrict the lumen of the vessel when they contract. Because bapwv was influenced by age, blood pressure, and duration of diabetes, we adjusted for these factors by logistic regression analysis. Our results showed that bapwv was associated with the risk of diabetic retinopathy, albuminuria, peripheral neuropathy, and decreased CV R-R at rest. In contrast, carotid PWV was unrelated to any diabetic complication. Several studies have reported that PWV correlates with diabetic complications. Regarding nephropathy, Tanokuchi et al. reported that aortic PWV was related to serum creatinine level in patients with type 2 diabetes mellitus (14). Regarding neuropathy, aortic PWV was reported to be correlated

812 Hypertens Res Vol. 26, No. 10 (2003) with expiratory to inspiratory R-R interval ratios in patients with type 2 diabetes mellitus (15). There has been no paper which has reported on the relation between retinopathy and PWV. We found that bapwv was significantly related to the presence or absence of diabetic complications. Comparable strong correlations of diabetic complications with other types of PWV, especially aortic PWV, have not been reported previously. Our results indicate that the clinical significance of ba- PWV may differ from that of carotid PWV and aortic PWV, which principally reflect the properties of elastic vessels. This finding suggests that bapwv may be a useful index of atherosclerosis associated with higher degrees of microangiopathy. As compared with carotid PWV or aortic PWV, bapwv has four main characteristics: 1) Since bapwv is determined on the basis of pulse waves measured at the upper arm and the ankles, the effects of peripheral vessels are greater than in carotid or aortic PWV; 2) The distance of bapwv is about 1.5 times greater than that of carotidfemoral PWV; 3) Both muscular vessels and elastic vessels are included; and 4) bapwv is substantially affected by vasomotor reflex. These characteristics may explain why bapwv more strongly correlates with diabetic complications than does aortic PWV. Aso et al. reported that vasomotor reflexes in the lower limbs were markedly impaired in diabetic patients (16). They suggested that diabetic autonomic neuropathy might lead to impaired sympathetic vasomotor activity. Furthermore, Scarpello et al. reported that PWV predominantly affects the lower limb arteries rather than the upper limb vessels in diabetic patients (17). Therefore, bapwv, which includes the lower limb arteries, may be more affected than carotid PWV in diabetic patients. The lack of a correlation between carotid PWV and diabetic complications might have been due to the distribution of angiopathy in patients with diabetes mellitus. The UK Prospective Diabetes Study (UKPDS) showed that strict blood pressure control (144/82 mmhg) decreases the risk of macrovascular complications such as stroke as well as the risk of microvascular complications as compared with less strict blood pressure control (154/87 mmhg) in patients with type 2 diabetes (18). These results have recently increased awareness that strict control of blood pressure is necessary to prevent the progression of macroangiopathy and microangiopathy in diabetic patients. Our study showed that bapwv, similar to blood pressure, correlated with microvascular complications. Furthermore, we reported previously that age and blood pressure are major determinants of bapwv (6). Therefore, assessment of bapwv may provide more useful information than measurement of blood pressure alone for the evaluation of microvascular complications. Arteriosclerosis obliterans (ASO) is an important complication of diabetes mellitus. The patients with ASO show the increased PWV in the early stage of ASO. With the progression of ASO, a lower ankle blood pressure in the ASO patients may be responsible for the decreased PWV in the lower extremities (19). The major limitation of our technique is that the pulse volume record and bapwv cannot be accurately determined in patients with severe atherosclerotic disease of the lower extremities. The increased arterial rigidity can be improved by antihypertensive drugs, especially calcium antagonists and angiotensin converting enzyme inhibitors (20). Wang et al. reported long-acting nitrates had potential value in improving large arterial distensibility in patients with essential hypertension (21). Therefore, the long-term effect of vasodilating drugs on PWV could not be excluded in our study. However, in order to limit the short-term effect of antihypertensive drugs on blood pressure lowering and PWV, no medications were taken on the morning of PWV measurement. Technically, bapwv can be simply measured by oscillometry on a routine basis, and we showed that increased bapwv and blood pressure correlated with microangiopathy in type 2 diabetic patients. Our results suggest that bapwv is useful for the assessment of patients with type 2 diabetes. References 1. Woolam GL, Schnur PL, Vallbona C, Hoff HE: The pulse wave velocity as an early indicator of atherosclerosis in diabetic subjects. Circulation 1962; 25: 533 539. 2. Blacher J, Asmar R, Djane S, London GM, Safar ME: Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients. Hypertension 1999; 33: 1111 1117. 3. Moritani T, Crouse SF, Shea CH, Davidson N, Nakamura E: Arterial pulse wave velocity, Fourier pulsatility index, and blood lipid profiles. Med Sci Sports Exerc 1987; 19: 404 409. 4. Blacher J, Guerin AP, Pannier B, et al: Impact of aortic stiffness on survival in end-stage renal disease. Circulation 1999; 99: 2434 2439. 5. Hasegawa M, Nagao K, Kinoshita Y, Rodbard D, Asahira A: Increased pulse wave velocity and shortened pulse wave transmission time in hypertension and aging. Cardiology 1997; 88: 147 151. 6. Kubo T, Miyata M, Minagoe S, Setoyama S, Maruyama I, Tei C: A simple oscillometric technique for determining new indices of arterial distensibility. Hypertens Res 2002; 25: 351 358. 7. American Diabetes Association: Clinical practice recommendations. Diabetes Care 1999; 22(Suppl 1): S11 S15. 8. 1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension, Guidelines Subcommittee: 1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension. J Hypertens 1999; 17: 151 183. 9. American Diabetes Association: Clinical practice recommendations. Diabetes Care 1999; 22(Suppl 1): S56 S59. 10. American Diabetes Association: Clinical practice recommendations. Diabetes Care 1999; 22(Suppl 1): S66 S69. 11. Nagai Y, Sugiyama Y, Abe T, Nomura G: 4-g monofilament is clinically useful for the detection of diabetic peripheral neuropathy. Diabetes Care 2001; 24: 183 184.

Aso et al: Aortic Stiffness and Diabetic Complications 813 12. Sasaki H, Nanjo K, Yamada M, et al: Diabetic neuropathy as a heterogeneous syndrome: multivariate analysis of clinical and neurological findings. Diabetes Res Clin Pract 1988; 4: 215 222. 13. Yamashina A, Tomiyama H, Takeda K, et al: Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement. Hypertens Res 2002; 25: 359 364. 14. Tanokuchi S, Okada S, Ota Z: Factors related to aortic pulse-wave velocity in patients with non-insulin-dependent diabetes mellitus. J Int Med Res 1995; 23: 423 430. 15. Okada S, Ishii K, Hamada H, et al: Relationship between cardiac autonomic neuropathy and diabetic microangiopathies and macroangiopathy in patients with non-insulin-dependent diabetes mellitus. J Int Med Res 1996; 24: 92 98. 16. Aso Y, Inukai T, Takemura Y: Evaluation of skin vasomotor reflexes in response to deep inspiration in diabetic patients by laser Doppler flowmetry: a new approach to the diagnosis of diabetic peripheral autonomic neuropathy. Diabetes Care 1997; 20: 1324 1328. 17. Scarpello JHB, Martin TRP, Ward JD: Ultrasound measurements of pulse-wave velocity in the peripheral arteries of diabetic subjects. Clin Sci 1980; 58: 53 57. 18. UK Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes, UKPDS 38. Br Med J 1998; 317: 703 713. 19. Suzuki E, Kashiwagi A, Nishio Y, et al: Increased arterial wall stiffness limits flow volume in the lower extremities in type 2 diabetic patients. Diabetes Care 2001; 24: 2107 2114. 20. Safar ME, Levy BI, Laurent ST, et al: Hypertension and the arterial system: clinical and therapeutic aspects. J Hypertens 1990; 8 (Suppl 7): S113 S119. 21. Wang H, Hu D, Sun N, Gong L, Zhang W: Effect of longacting isosorbide-5-mononitrate administration on large artery distensibility in patients with essential hypertension. Hypertens Res 2001; 24: 311 314.