Relationship of medial arterial calcinosis to autonomic neuropathy and adverse outcomes in a diabetic veteran population☆
Introduction
Medial arterial calcinosis (MAC), defined as calcification of the media of arterial walls, is found primarily in persons with diabetes and is associated with advancing age, duration of diabetes, peripheral neuropathy, and other diabetic complications Edmonds et al., 1982, Everhart et al., 1988, Young et al., 1993. The development of ipsilateral MAC has also been described in nondiabetic persons who have undergone a unilateral sympathectomy (Goebel & Fuessl, 1983), suggesting the pathophysiology may involve peripheral autonomic neuropathy. The calcification first appears in vessels of the foot, then progresses proximally over time Everhart et al., 1988, Young et al., 1993 and develops independently of atherosclerosis of the intima (Schinke, McKee, Kiviranta, & Karsenty, 1998). The only population-based evaluation of MAC comes from the Pima Indians, where the prevalence was found to be over 50% by age 65 in persons with diabetes (Everhart et al., 1988). MAC is often noted incidentally on radiographs, but calcification can also be noted on duplex ultrasound of the vessels and may flatten pulse volume waveforms. The development of MAC within 4 years of the diagnosis of diabetes in the Pima Indians was strongly associated with an increased risk of amputation, macroproteinuria, retinopathy, and death (Everhart et al., 1988).
The presence of autonomic neuropathy has also been associated with a number of adverse outcomes for persons with diabetes. The evidence includes an association with foot ulceration in several cross-sectional studies Aso et al., 1998, Edmonds et al., 1986, Gilmore et al., 1993 and with mortality Stevens et al., 1998, Töyry et al., 1996, Weston & Gill, 1999.
MAC may be a risk factor for these adverse outcomes. However, it may be merely a marker—a condition that is linked to a risk factor, but on its own is not a risk factor. We hypothesized that the adverse outcomes associated with MAC are due to the presence of autonomic neuropathy and MAC is a marker of this significant risk factor. Thus, we undertook this evaluation of a cohort of diabetic veterans to determine if the observed increase in lower extremity ulceration, amputation, and mortality in persons with MAC could be explained by the presence of autonomic neuropathy.
Section snippets
Design
We conducted a secondary analysis of longitudinal data collected on a diabetic veteran cohort at the Veterans Administration Puget Sound Health Care System (Seattle, WA). The original data collection and our study were both approved by the Puget Sound Health Care System's Research Committee and the University of Washington Investigation and Research Board.
Case identification
Between October 1990 and April 1993, 707 ambulatory patients at the Veterans Affairs Puget Sound Health Care System (Seattle facility) with
Demographic and clinical factors associated with MAC
MAC was present in 181 veterans (42%) and absent in 253 veterans (58%) at baseline. The subjects with MAC were older when compared to those without MAC (65.8 vs. 63.0 years, P=.0036), diagnosed with diabetes at a younger age (49.5 vs. 52.5 years, P=.025), and thus had a longer duration of diabetes (15.4 vs. 9.5 years, P<.0001). The subjects with MAC were more likely to have Type 1 diabetes (11% vs. 3%, P=.004) and were more likely to be insulin treated (57% vs. 42%, P=.012). The two groups
Discussion
The presence of MAC has been firmly associated with neuropathy due to diabetes Edmonds et al., 1982, Everhart et al., 1988, Young et al., 1993, other neuropathic syndromes, and unilateral surgical sympathectomy (Goebel & Fuelss, 1983). In 1982, Edmonds et al. suggested that autonomic neuropathy might be an important etiologic factor for MAC, after noting the high association of MAC in persons with diabetic neuropathy and the observation that experimental denervation of vascular smooth muscle
Acknowledgements
We thank John Harley M.D. for his assistance with the review of radiographs and Sally Swedine for her assistance with the figures.
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This research was supported by the Department of Veterans Affairs, Veterans Health Administration, Seattle Epidemiologic Research and Information Center (ERIC).