Association Between Cardiovascular Autonomic
Neuropathy and Left Ventricular Dysfunction
DCCT/EDIC Study (Diabetes Control and Complications
Trial/Epidemiology of Diabetes Interventions and Complications)
Rodica Pop-Busui, MD, PHD,* Patricia A. Cleary, MS,† Barbara H. Braffett, MS,†
Catherine L. Martin, MS, RN,* William H. Herman, MD, MPH,* Phillip A. Low, MD,‡
Joao A. C. Lima, MD, PHD,§ David A. Bluemke, MD, PHD,? for the DCCT/EDIC Research Group
Ann Arbor, Michigan; Rockville, Baltimore, and Bethesda, Maryland; and Rochester, Minnesota
The goal of these studies was to determine the association between cardiovascular autonomic neuropathy (CAN)
and indices of left ventricle (LV) structure and function in patients with type 1 diabetes (T1DM) in the DCCT/EDIC
(Diabetes Control and Complications Trial /Epidemiology of Diabetes Interventions and Complications) study.
The pathophysiology of LV dysfunction in T1DM remains unclear, especially when the LV ejection fraction (EF) is
preserved. Whether CAN is associated with LV dysfunction is unclear.
Indices of LV structure and function were obtained by cardiac magnetic resonance imaging (CMRI). CAN was
assessed by cardiovascular reflex testing (R-R response to paced breathing, Valsalva ratio, and blood pressure
response to standing). Analyses were performed in 966 DCCT/EDIC participants with valid CMRI and CAN data
(mean age 51 years, 52% men, mean diabetes duration 29 years, and mean glycosylated hemoglobin 7.9%).
Systolic function (EF, end-systolic and end-diastolic volumes, stroke volumes) was not different in 371 subjects
with CAN compared with 595 subjects without CAN. In multiple-adjusted analyses, participants with either ab-
normal R-R variation or a composite of abnormal R-R variation, abnormal Valsalva ratio, and postural blood
pressure changes had significantly higher LV mass, mass-to-volume-ratio, and cardiac output compared with
those with normal tests (p ? 0.0001 for all). After further adjustment for traditional cardiovascular risk factors,
subjects with abnormal R-R variation had higher LV mass and cardiac output compared with those with a nor-
mal R-R variation (p ? 0.05).
In this large cohort of patients with T1DM, CAN is associated with increased LV mass and concentric remodeling
as assessed by CMRI independent of age, sex, and other factors. (Diabetes Control and Complications Trial [DCCT];
NCT00360815) (Epidemiology of Diabetes Interventions and Complications [EDIC]; NCT00360893)
Coll Cardiol 2013;61:447–54) © 2013 by the American College of Cardiology Foundation
Cardiovascular disease (CVD) is a major cause of mortality
among patients with type 1 diabetes (T1DM). In T1DM,
left ventricular (LV) dysfunction may precede or occur in
the absence of coronary artery disease or hypertension, often
seen in the setting of a normal ejection fraction (EF) (1–4),
and its pathophysiology remains unclear. Diastolic dysfunc-
tion, characterized by impairment in LV relaxation and
passive filling, was reported as the earliest manifestation of
diabetic cardiomyopathy (2,5). Our group has found that
diastolic dysfunction detected early in the course of T1DM
is correlated with abnormal cardiac sympathetic function as
assessed by cardiac sympathetic imaging (4). Cardiovascular
autonomic neuropathy (CAN) complicates T1DM and is
an independent predictor of mortality in affected patients
From the *Division of Metabolism, Endocrinology and Diabetes, University of Michi-
gan, Ann Arbor, Michigan; the †Biostatistics Center, George Washington University,
Rockville, Maryland; ‡Department of Neurology, Mayo Clinic, Rochester, Minnesota;
§Division of Cardiology, Johns Hopkins University, Baltimore, Maryland; and ?Radi-
ology and Imaging Sciences, National Center for Biomedical Imaging and Bioengineer-
ing, National Institutes of Health, Bethesda, Maryland. The DCCT/EDIC project is
supported by contracts with the Division of Diabetes, Endocrinology and Metabolic
Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases;
National Eye Institute; National Institute of Neurological Disorders and Stroke; the
General Clinical Research Centers Program; and the Clinical and Translation Science
Centers Program, National Center for Research Resources, as well as by Genentech
of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland. The authors have
reported that they have no relationships relevant to the contents of this paper to disclose.
Darren McGuire, MD, served as Guest Editor of this paper.
Manuscript received September 4, 2012; accepted October 23, 2012.
Journal of the American College of Cardiology
© 2013 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 61, No. 4, 2013
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Key Words: cardiovascular autonomic neuropathy y left ventricle
hypertrophy y myocardial dysfunction y type 1 diabetes.
For supplemental tables and a list of the participating radiologists and
technologists in the DCCT/EDIC Research Group, please see the Online
Appendix. A complete list of the individuals and institutions participating in
the DCCT/EDIC Research Group can be found in Archives of Ophthalmol-
454 Pop-Busui et al.
Autonomic Neuropathy and LV Dysfunction in Diabetes
JACC Vol. 61, No. 4, 2013
January 29, 2013:447–54