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Autoantibodies to Autonomic Nerves Associated With Cardiac and Peripheral Autonomic Neuropathy

¹ Department of Clinical Sciences, Lund University, Malmö University Hospital, Malmö, Sweden
² Department of Endocrinology M, Aarhus University Hospital, Aarhus, Denmark
³ Department of Immunobiology, Guy’s, King’s, and St. Thomas School of Medicine, King’s College, London, U.K.

Address correspondence and reprint requests to Viktoria Granberg, MD, Department of Endocrinology, Wallenberg Laboratory, Entrance 46, 2nd floor, Malmö University Hospital, S-20502 Malmö, Sweden. E-mail: viktoria.granberg{at}endo.mas.lu.se

OBJECTIVE—This study examines whether autonomic nerve autoantibodies (ANabs) are associated with development of autonomic neuropathy using a prospective study design.

RESEARCH DESIGN AND METHODS—A group of type 1 diabetic patients were followed prospectively with regard to autonomic nerve function on four occasions. At the third examination, 41 patients were tested for ANabs (complement-fixing autoantibodies to the sympathetic ganglion, vagus nerve, and adrenal medulla), and the results were related to cardiac autonomic nerve function (heart rate variation during deep breathing [expiration/inspiration ratio] and heart-rate reaction to tilt [acceleration and brake index]) and to peripheral sympathetic nerve function (vasoconstriction after indirect cooling [vasoconstriction index]).

RESULTS—ANabs were detected in 23 of 41 (56%) patients at the third examination. Compared with patients without ANabs (ANabs^–), patients with ANabs (ANabs⁺) showed significantly higher frequencies of at least one abnormal cardiac autonomic nerve function test at the third examination (17 of 23 [74%] vs. 7 of 18 [39%]; P = 0.03) and fourth examination (15 of 21 [71%] vs. 4 of 16 [25%]; P < 0.01). In contrast, there was no similar difference at the first or second examination. The relative risk for ANabs⁺ patients to develop cardiac autonomic neuropathy at follow-up was 7.5 (95% CI 1.72–32.80). The vasoconstriction index was more abnormal in ANabs⁺ than in ANabs^– patients at the fourth examination (median 1.40 [interquartile range 1.58] vs. 0.35 [2.05]; P = 0.01).

CONCLUSIONS—ANabs were associated with future development of cardiac and peripheral autonomic neuropathy in diabetic patients, implying an etiological relationship between nervous tissue autoimmunity and these diabetes complications.

Abbreviations: ANab, autonomic nerve autoantibody • E/I, expiration/inspiration • ICA, islet cell antibody • LDI, laser Doppler imaging

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