Ankle-Brachial Index: a Surrogate Marker of Microvascular Complications in Type 2 Diabetes Mellitus?
By Papanas, N Symeonidis, G; Mavridis, G; Georgiadis, G S; Papas, T T; Lazarides, M K; Maltezos, E
Aim. The aim of this study was to investigate the potential role of ankle-brachial index (ABI) as a marker of microvascular disease in patients with type 2 diabetes mellitus. Methods. This study included 126 type 2 diabetic patients (64 male and 62 female) with an age of 66.6+-5.3 years (mean+-SD) and diabetes duration of 13.2+- 4.1 years. ABI was measured with a Doppler device. The exclusion criterion was the medial arterial calcification. Patients were also examined for microalbuminuria, retinopathy and peripheral neuropathy.
Results. ABI was significantly lower in patients with microalbuminuria than in those without microalbuminuria (0.91 +- 0.17 vs 1.05+-0.13, P=0.004), in patients with retinopathy than in those without retinopathy (0.91 +-0.18 vs 1.06+-0.1, P=0.005), as well as in patients with neuropathy than in those without neuropathy (0.94+-0.17 vs 1.06+-0.11, P=0.001). Sensitivity and specificity of ABI <0.9 were 48.8% and 87.9% respectively for microalbuminuria, 39.1% and 93% respectively for retinopathy and 47% and 90.7% respectively for neuropathy. In multiple regression analysis, significant predictor of microalbuminuria was diabetes duration (P=0.0014), significant predictor of retinopathy was diabetes duration (P=0.001), while significant predictors of neuropathy were diabetes duration (P=0.001), male sex (PsO.001) and presence of retinopathy (P=0.047).
Conclusion. ABI is significantly lower in patients with than in those without microvascular complications of type 2 diabetes. An ABI <0.9 has a low to modest sensitivity, but a high specificity for the diagnosis of these complications. Our results suggest a potential role for ABI as a surrogate marker of microvascular complications in type 2 diabetic patients.
[Int Angiol 2007;26:253-7]
Key words: Ankle-Brachial Index – Diabetes mellitus – Ultrasonography, Doppler, Duplex – Microvasculature.
Ankle-brachial index (ABI) is a widely used, standardized diagnostic test for peripheral arterial disease (PAD).1-3 It has been validated in large epidemiological studies 4-7 and has been found to have a high reproducibility.8-9 Its use in patients with diabetes mellitus has been criticized, because medial arterial calcification may cause spuriously elevated ankle pressures.1 3, 10- 12 Nonetheless, it has been shown that ABI may be reliably used in diabetic patients, with the exception of those with ABI higher than a critical value, suggestive of medial calcification.13,14
Several studies have also established ABI as a marker of cardiovascular morbidity.4-5, 15-17 This is mainly attributed to ischemic heart disease, prompting some authors to suggest that a low ABI is a diagnostic tool for coronary artery disease (CAD).18-22 The association between PAD and CAD is particularly relevant in patients with diabetes.23-25 Interestingly, not only is a low ABI a marker of CAD, but it is also a predictor of its angiographic severity, both in diabetic and in non-diabetic patients.26-27
However, while ABI is an accepted marker of atherosclerotic macrovascular disease in diabetic patients, its role as a marker of microvascular disease has, to the best of our knowledge, not been investigated. Thus, the aim of the present study was to examine the potential role of ABI as a marker of microvascular disease in patients with type 2 diabetes mellitus.
Materials and methods
This study included 126 type 2 diabetic patients (64 male, 62 female) with an age of 66.6+-5.3 years (mean+-SD) and diabetes duration of 13.2+-4.1 years. These were recruited from the Diabetic Department of the O Agios Dimitrios General Hospital of Thessaloniki, Greece. Patient characteristics are shown in Table I. The study was performed in accordance with the Helsinki Declaration of Human Rights and all patients gave their informed consent.
ABI was measured using a Doppler device (PROGETTI 2000). Systolic pressure was measured both in the dorsalis pedis and in the posterior tibial artery. The higher value of these pressures was divided by the higher value of the two brachial systolic pressures to calculate ABI. ABI was measured in both limbs and the lower of the two values was used for the analysis.1-3 Patient examination was performed in normal room temperature (25 [degrees]C) after patients had taken off their shoes and socks and had been allowed a 10-min rest. Doppler examination was conducted by an operator who was blinded to the patients’ characteristics and to the presence or absence of microvascular complications. PAD was diagnosed in patients with an ABI <0.9.1-3, 28
The exclusion criterion was the presence of medial arterial calcification, defined as ABI >/=1.3 or visible arterial calcification on plain X-rays.3-4
Patients were also evaluated for microalbuminuria, retinopathy and peripheral neuropathy. Microalbuminuria was defined as an albumin excretion rate >/=20 [mu]g/min, in the absence of uncontrolled hypertension and/or urinary tract infection.29 Retinopathy was defined as at least two microaneurysms and/or retinal hemorrhage and/or other signs of retinal damage.30 Diabetic neuropathy was diagnosed by the neuropathy disability score (NDS).31 This is a standardized clinical examination of ankle reflexes as well as 128 Hz tuning fork, pin-prick and temperature (cold tuning fork) sensation at the hallux, as described earlier.31 Diagnosis of neuropathy was defined as an NDS >/=6.31,32
Statistical analysis was conducted using the SPSS (Statistical Package for Social Sciences) 11.0. In univariate analysis, normally distributed quantitative variables were analysed by unpaired t- test. Multivariate logistic regression analysis, using each of the microvascular complications (neuropathy, microalbuminuria and neuropathy) separately as a dependent variable, was also performed. Significance was defined at the 5% level (P<0.05).
ABI was significantly lower in patients with microalbuminuria than in those without microalbuminuria (0.91 +-0.17 vs 1.05+-0.13, P=0.004) (mean+-SD), in patients with retinopathy than in those without retinopathy (0.91 +-0.18 vs 1.06+-0.1, P=0.005), as well as in patients with neuropathy than in those without neuropathy (0.94+- 0.17 vs 1.06+-0.11, P=0.001). Longer duration of diabetes (>10 years) was also significantly associated with lower ABI as compared to shorter duration of diabetes (=10 years) (0.97+-0.17 vs 1.07+- 0.1, P=0.005).
PAD was diagnosed in 21/43 (48.8%) patients with microalbuminuria and 10/83 (32.3%) patients without microalbuminuria. Sensitivity and specificity of ABI <0.9 for microalbuminuria were 48.8% and 87.9%, respectively. Positive prognostic value was 67.7% and negative prognostic value was 76.8%. PAD was diagnosed in 27/69 (39.1%) patients with retinopathy and 4/57 (7%) patients without retinopathy. Sensitivity and specificity of ABI <0.9 for retinopathy were 39.1% and 93%, respectively. Positive and negative prognostic values were 87.1% and 93%, respectively. PAD was diagnosed in 24/51 patients (47%) with neuropathy and 7/75 patients (8.7%) without neuropathy. Sensitivity, specificity, positive and negative prognostic values of ABI <0.9 for neuropathy were 47%, 90.7%, 77.4% and 71.6%, respectively.
Significant predictors of microvascular complications, as identified by multivariate logistic regression analysis, are shown in Table II.
The present study demonstrated that ABI was significantly lower in type 2 diabetic patients with microalbuminuria than in those without microalbuminuria. An ABI <0.9 had a modest sensitivity (48.8%) and a high specificity (87.9%) for microalbuminuria. The association between ABI and microalbuminuria has not been investigated. Our findings, however, are in line with the notion that microalbuminuria is an index of generalized vascular disease, both in type 1 and in type 2 diabetes.33-35 According to this concept (originally formulated as the Steno hypothesis), microalbuminuria reflects pronounced endothelial dysfunction, which, in turn, is accountable for widespread micro- and macrovascular disease.33-35 In this context, it is not surprising that patients with microalbuminuria have a lower ABI and that ABI may contribute to the indirect diagnosis of microalbuminuria.
Similarly, retinopathy was associated with a significantly lower ABI. An ABI <0.9 had a low sensitivity (39.1%), but a very high specificity (93%) for retinopathy. This association has not been reported. There is evidence to suggest that diabetic retinopathy may be more frequent in patients with cardiovascular disease, in particular increased common carotid artery intima-media thickness 36 37 and diffuse CAD.38 This work found that retinopathy was connected with PAD, a further manifestation of large-vessel disease.
Moreover, neuropathy was associated with a significantly lower ABI. An ABI <0.9 had a modest sensitivity (47%), but a very high specificity (90.7%) for neuropathy. Certainly, neuropathy is known to be associated with medial arterial calcification,39,40 which, in turn, leads to falsely elevated ABI.1, 3, 10, 12, 40 This, however, was not the case in the present study, since patients with medial arterial calcification were excluded. It has also been suggested that neuropathy may impair blood flow to the foot, leading to a reduction of toe pressure,41 but this has not been confirmed.42 Our findings would rather point to an association between neuropathy and PAD, as shown in a more recent study.43 In multivariate logistic regression analysis, diabetes duration emerged as the most significant predictor of microvascular complications. This held true for retinopathy, microalbuminuria and neuropathy, in keeping with established knowledge that frequency of chronic complications is associated with disease duration.29, 30, 44 Neuropathy was also significantly associated with male sex and presence of retinopathy. The association of neuropathy with these two parameters has been found in some, but not all, epidemiological studies.44, 45 Interestingly, no association between PAD, as diagnosed by ABI, and microvascular complications was demonstrated. It appears, therefore, that ABI may be of value as surrogate marker of microvascular complications, while it is not a significant predictor of their presence.
The practical implications of our findings may be summarized as follows. An ABI <0.9 has a low to modest sensitivity, but is highly specific for the diagnosis of microvascular complications in type 2 diabetes. Hence, a low ABI may be interpreted with a high index of suspicion for the presence of microvascular disease. Given that it is an easy-to-use and reproducible diagnostic tool,1,3,9 it may be anticipated that ABI could help diagnosis of microvascular complications and prompt appropriate diagnostic work-up.
In conclusion, ABI is significantly lower in patients with than in those without microvascular complications of type 2 diabetes. An ABI <0.9 has a low to modest sensitivity, but a high to very high specificity for the diagnosis of these complications.
These results suggest a potential role for ABI as a surrogate marker of microvascular complications in type 2 diabetic patients.
Received on October 4, 2006; acknowledged on November 15, 2006; accepted for publication on January 5, 2007.
1. Dormandy JA, Rutherford RB. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Consensus (TASC). J Vase Surg 2000:31(1 Pt 2):S1-S296.
2. AbuRahma AF. Segmental Doppler pressures and Doppler waveform analysis in peripheral vascular disease of the lower extremities. In: AbuRahma AF, Bergan JJ, editors. Nonivasive vascular diagnosis. London: Springer-Verlag; 2000.p.213-29.
3. Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med 2001;344:1608-21.
4. Fowkes FG, Housley E, Cawood EHH, Macintyre CC, Ruckley CV, Prescott RJ. Edinburgh artery study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. Lit J Epidemiol 1991;20:384-92.
5. Ogren M, Hedblad B, Jungquist G, Isacsson SO, Lindell SE, Janzon L. Low Ankle-Brachial Pressure Index in 68year-old men: Prevalence, risk factors and prognosis. Eur J Vasc Surg 1993;7:500- 6.
6. Dormandy J, Heeck L, Vig S. Intermittent claudication: a condition with underrated risks. Semin Vase Surg 1999;12:96-108.
7. Meijer WT, Grobbee DE, Hunink MG, Hofman A, Hoes AW. Determinants of peripheral arterial disease in the elderly: the Rotterdam study. Arch Intern Med 2000;160:2934-8.
8. Fowkes FG, Housley E, Macintyre CC, Prescott RJ, Ruckley CV. Variability of ankle and brachial systolic pressures in the measurement of atherosclerotic peripheral arterial disease. J Epidemiol Community Health 1988;42:128-33.
9. Stoffers J, Kaiser V, Kester A, Schouten H, Knottnerus A. Peripheral arterial occlusive disease in general practice: the reproducibility of the ankle-arm systolic pressure ratio. Scand J Prim Health Care 1991;9:109-14.
10. Goebel FD, Fuessl HS. Monckeberg’s sclerosis after sympathetic denervation in diabetic and non-diabetic subjects. Diabetologia 1983;24:347-50.
11. Orchard TJ, Strandness DE Jr. Assessment of peripheral vascular disease in diabetes. Report and recommendations of an International Workshop sponsored by the American Heart Association and the American Diabetes Association 18-20 September 1992, New Orleans, Louisiana. J Am Podiatr Med Assoc 1993;83:685-95.
12. Williams DT, Harding KG, Price P. An evaluation of the efficacy of methods used in screening for lower-limb arterial disease in diabetes. Diabetes Care 2005;28:2206-10.
13. Apelqvist J, Bakker K, van Houtum WH, Nabuurs-Fransen MH, Schaper NC. International consensus and practical guidelines on the management and the prevention of the diabetic foot: International Working Group on the Diabetic Foot. Diabetes Metab Res Rev 2000; 16 Suppl 1:S84S92.
14. Brooks P, Dean R, Patel S, Wu B, Molyneaux L, Yue DK. TBI or not TBI: that is the question. Is it better to measure toe pressure than ankle pressure in diabetic patients? Diabet Med 2001;18:528- 32.
15. Kornitzer M, Dramaix M, Sobolski J, Degre S, De Backer G. Ankle/arm pressure index in asymptomatic middleaged males: an independent predictor of ten-year coronary heart disease mortality. Angiology 1995;46:211-9.
16. Leng GC, Fowkes FG, Lee AJ, Dunbar J, Housley E, Ruckley CV. Use of ankle brachial pressure index to predict cardiovascular events and death: a cohort study. BMJ 1996;313:1440-4.
17. Zheng ZJ, Sharrett AR, Chambless LE, Rosamond WD, Nieto FJ, Sheps DS et al. Associations of ankle-brachial index with clinical coronary heart disease, stroke and preclinical carotid and popliteal arthrosclerosis: the Atherosclerosis Risk in Communities (ARIC) Study. Arthrosclerosis 1997;131:115-25.
18. McKenna M, Wolfson S, Kuller L. The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Atherosclerosis 1991;87:119-28.
19. Newman AB, Siscovick DS, Manolio TA, Polak J, Fried LP, Borhani NO et al. Ankle-Arm Index as a marker of atherosclerosis in the Cardiovascular Health Study. Circulation 1993;88:837-45.
20. Cimminiello C. Peripheral arterial disease as a global risk factor. Haematologica 2001;86:16-8.
21. Criqui M. Peripheral arterial disease: epidemiological aspects. Vasc Med 2001;6 Suppl 1:3-7.
22. Pearson TA. New tools for coronary risk assessment. What are their advantages and limitations? Circulation 2002;105:886-92.
23. American Diabetes Association. Consensus development conference on the diagnosis of coronary heart disease in people with diabetes: 10-11 February 1998, Miami, Florida. American Diabetes Association. Diabetes Care 1998;21:1551-9.
24. Birrer M. Macroangiopathy in diabetes mellitus. VASA 2001;30:168-74.
25. Belch JJF. Metabolic, endocrine and haemodynamic risk factors in the patient with peripheral arterial disease. Diabetes Obes Metab 2002;4 Suppl 2: S7-S13.
26. Papamichael CM, Lekakis JP, Stamatelopoulos KS, Papaioannou TG, Alevizaki MK, Cimponeriu AJ et al. AnkleBrachial Index as a predictor of the extent of coronary atherosclerosis and cardiovascular events in patients with coronary artery disease. Am J Cardiol 2000;86:615-8.
27. Papanas N, Tziakas D, Maltezos E, Kekes A, Hatzinikolaou E, Parcharidis G et al. Peripheral arterial occlusive disease as a predictor of the extent of coronary atherosclerosis in patients with coronary artery disease with and without diabetes mellitus. J Int Med Res 2004;32: 422-8.
28. Klein S, Hage JJ. Measurement, calculation, and normal range of the Ankle-Arm Index: a bibliometric analysis and recommendation for standardization. Ann Vasc Surg 2006;20:282-92.
29. American Diabetes Association. Diabetic nephropathy. Position statement. Clinical practice recommendations 2003. Diabetes Care 2003;26 Suppl 1:S94-S98.
30. Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, Cavallerano JD et al. Diabetic retinopathy. Position statement. Clinical practice recommendations 2003. Diabetes Care 2003;26 Suppl LS99-S102.
31. Young M, Boulton AJM, McLeod AF, Williams DRR, Sonksen PH. a multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom Hospital clinic population. Diabetologia 1993;36:150-4.
32. Paisley AN, Abbott CA, van Schie CHM, Boulton AJM. A comparison of the Neuropen against standard quantitative sensory- threshold measures for assessing peripheral nerve function. Diabet Med 2002;19:400-5.
33. Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A. Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia 1989;32:219-26.
34. Deckert T, Kofoed-Enevoldsen A, Norgaard K, BorchJohnsen K, Feldt-Rasmussen B, Jensen T. Microalbuminuria. Implications for micro- and macrovascular disease. Diabetes Care 1992;15:1181-91.
35. Deckert T, Yokoyama H, Mathiesen E, Ronn B, Jensen T, Feldt- Rasmussen B et al. Cohort study of predictive value of urinary albumin excretion for atherosclerotic vascular disease in patients with insulin dependent diabetes. BMJ 1996;312:871-4.
36. Klein R, Sharrett AR, Klein BE, Moss SE, Folsom AR, Wong TY et al. The association of atherosclerosis, vascular risk factors, and retinopathy in adults with diabetes: the atherosclerosis risk in communities study. Ophthalmology 2002;109:1125-34.
37. Klein R, Marino EK, Kuller LH, Polak JF, Tracy RP, Gottdiener JS et al. The relation of atherosclerotic cardiovascular disease to retinopathy in people with diabetes in the Cardiovascular Health Study. Br J Ophthalmol 2002;86:84-90.
38. Norgaz T, Hobikoglu G, Aksu H, Guveli A, Aksoy S, Ozer O et al. Retinopathy is related to the angiographically detected severity and extent of coronary artery disease in patients with type 2 diabetes mellitus. Int Heart J 2005;46:639-46.
39. Gilbey SG, Walters H, Edmonds ME, Archer AG, Watkins PJ, Parsons V et al. Vascular calcification, autonomic neuropathy, and peripheral blood flow in patients with diabetic nephropathy. Diabet Med 1989; 6: 37-42.
40. Edmonds ME. Medial arterial calcification and diabetes mellitus. Z Kardiol 2000;89:Suppl 2:II/101-4.
41. Uccioli L, Monticone G, Durola L, Russo F, Mormile F, Mennuni G et al. Autonomic neuropathy influences great toe blood pressure. Diabetes Care 1994;17:284-7. 42. Stevens MJ, Goss DE, Foster AVM, Pitei D, Edmonds ME, Watkins PJ. Abnormal digital pressure measurements in diabetic neuropathic foot ulceration. Diabet Med 1993;10:909-15.
43. Edmonds ME, Foster AVM. Peripheral neuropathy may explain the distal distribution or atherosclerosis in the diabetic lower extremity. Diabetologia 2004 ;47 Suppl 1:A1044.
44. Boulton AJM, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies. Technical review. Diabetes Care 2004;27:1458- 86.
45. El-Asrar AM, Al-Rubeaan KA, Al-Amro SA, Moharram OA, Kangave D. Retinopathy as a predictor of other diabetic complications. Int Ophthalmol 2001;24:1-11.
N. PAPANAS 1, G. SYMEONIDIS2, G. MAVRIDIS2, G. S. GEORGIADIS3
T. T. PAPAS 3, M. K. LAZARIDES3, E. MALTEZOS 1
1 Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece
2 Diabetic Department, O Agios Dimitrios General Hospital, Thessaloniki, Greece
3 Department of Vascular Surgery, Democritus University of Thrace, Alexandroupolis, Greece
Address reprint requests to: Dr. N. Papanas, Ethnikis Antistasis 44, Alexandroupolis 68100, Greece.
E-mail to: firstname.lastname@example.org
Copyright Edizioni Minerva Medica Sep 2007
(c) 2007 International Angiology. Provided by ProQuest Information and Learning. All rights Reserved.