Relationship of medial arterial calcinosis to autonomic neuropathy and adverse outcomes in a diabetic veteran population

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Abstract

Statement of the problem: Medial arterial calcinosis (MAC) is associated with neuropathy, amputation, and mortality through an unknown mechanism. We hypothesized that MAC was a marker of autonomic neuropathy rather than a risk factor and that the outcomes were due to autonomic neuropathy. Methods: All subjects in an ongoing prospective study of diabetic foot conditions in a diabetic veteran cohort who received a foot radiograph between 11/7/90 and 11/5/93 were included. Autonomic neuropathy measured as either heart rate variability with timed respiration or postural hypotension. A logistic model predicted the presence of MAC at baseline and Cox proportional models assessed the relative contribution of autonomic neuropathy and traditional risk factors for the outcomes of ulceration, amputation, and death. Results: MAC was identified in 181 subjects, no MAC in 253 subjects, and 39 were excluded due to disagreement between observers. Both measures of autonomic neuropathy were independent predictors of MAC at baseline, even after adjustment for vibration sensation loss in a logistic model. MAC was associated with an increased risk for ulceration (hazards ratio, HR: 2.1, 95% confidence intervals, CI, 1.4–3.1), amputation (HR 3.3, 95% CI 1.5–7.4), and mortality (HR 1.6, 95% CI 1.1–2.2). The addition of either autonomic measure of neuropathy did not change the MAC HR or significantly improved the fit of the model. Conclusions: Our hypothesis that the excess mortality, amputation, and ulceration in persons with MAC could be explained by autonomic neuropathy measured as postural hypotension or heart rate variability with measured respiration was not supported.

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).

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