Cardiovascular autonomic neuropathy, autonomic symptoms and diabetic complications in 674 type 2 diabetes

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Abstract

Aims

To determine the relationships between cardiovascular autonomic neuropathy (CAN) and autonomic symptoms, clinical parameters and diabetic complications in type 2 diabetes (T2DM).

Methods

The results of autonomic symptoms, clinical parameters, diabetes complications and cardiovascular reflex (CVR) tests of 674 T2DM were analyzed.

Results

Significant correlations were found between CAN risk and age (p = 0.019), duration of diabetes (p = 0.008), HbA1c (p < 0.001), systolic blood pressure (p = 0.006), nephropathy (p < 0.001), retinopathy (p < 0.001), and QTc interval (p < 0.001), but not BMI and hyperlipidemia. Patients with retinopathy or proteinuria had increase risk of CAN, and proliferative diabetic retinopathy (PDR) was the most significant risk factor (odds ratio: 6.85; 95% CI: 2.32–20.20) for CAN. Eighty-three percent of patients complained of autonomic symptoms; and the more symptoms complained, the higher the prevalence of CAN. Impotence was the only single symptom associated with CAN risk. Additional CAN risks were also observed when patients with multiple symptoms and/or complications in combinations.

Conclusions

Our results implied that patients with multiple symptoms and/or complications in combinations have increased CAN risk, and this may provide additional information for clinicians to identify T2DM at risk of having CAN.

Introduction

Autonomic neuropathy is a common complication of diabetes, which is often ignored by the physicians due to its insidious onset and not routinely tested in most diabetic clinics. The manifestations of diabetic autonomic neuropathy (DAN) are multiplex, depending on the severity of autonomic nervous system and organs involved. Cardiovascular autonomic neuropathy (CAN), the most conspicuous and important form of DAN, is found to have an increased risk of mortality in diabetes [1], [2], [3]. Although the exact pathogenesis of autonomic dysfunction is not clearly understood, it is believed that multiple factors are involved in the pathogenesis of neuronal damage [4], [5], [6], [7], [8]. Currently, no single therapeutic agent is available to restore the function of the damaged nerves in patients with DAN. Intensified treatment of type 2 diabetes (T2DM) targeting hyperglycemia, hypertension, dyslipidemia, and microalbuminuria has been reported to reduce the risks of cardiovascular events, nephropathy, retinopathy, and autonomic neuropathy by about 50% [9]. Thus, understanding the risk factors and early detection of DAN is crucially important for the treatment strategies.

Many patients with DAN are asymptomatic, and self-reported autonomic-like symptoms may be caused by concomitant disorders other than DAN. The diagnosis of DAN based on the clinical symptoms is often unreliable. A series of cardiovascular reflex (CVR) tests to examine the heart rate variation (HRV) and blood pressure (BP) changes in response to different physiological stimulations are widely used for assessing CAN [10]. In this study, we analyzed a large sample of patients who were referred by diabetologists for CVR tests, to determine the relationships between CAN and the autonomic symptoms, clinical characteristics, metabolic status and chronic complications. The results may provide useful information for clinicians to identify patients who are at risk of CAN and refer them for autonomic function tests. Starting earlier the effective treatments targeting the concurrent risk factors may delay advanced autonomic neuropathy.

Section snippets

Patients

A total of 997 patients with T2DM, who complained of autonomic-like symptoms or presented with clinical manifestations suggested of DAN, were referred from a group attending diabetic clinic in the Taipei Veteran General Hospital for CVR tests during the period from May 2000 to August 2004. The medical records of these patients were carefully reviewed, 323 patients with history of heart, renal, liver, thyroid, neurological diseases, or taking medication known to affect the autonomic nervous

Abnormal CVR tests and CAN

The diagnostic criteria and the results of CVR tests are shown in Table 1. The prevalence of abnormal HRV in response to standing, SDB and 6DB were 70.9%, 53.0%, and 58.9%, respectively. Only one-quarter of patients met the diagnostic criteria of postural hypotension (PHT). Among subjects with PHT, 85% had at least one abnormal HRV test suggested that PHT is a late manifestation of CAN. According to our diagnostic criteria, 58% of the patients who had scores ≧3 were defined as having CAN.

Clinical and metabolic parameters

Table 2

Discussion

DAN screening has been recommended in patients with T2DM at diagnosis and 5 years after the diagnosis of type 1 diabetes [16]. CVR tests were suggested as the diagnostic tool for DAN by the San Antonio Conference [17]. However, the reported prevalence varies markedly from 15.8% to 73% in different studies [18], [19], [20]. The great variability in reported prevalence may be caused by different study populations, varied testing methods and lack of standardized criteria for the diagnosis of DAN.

Conflict of Interest

The authors state that they have no conflict of interest.

Acknowledgements

This work was supported by Taipei Veterans General Hospital Grant VGH-95-D003. The authors thank Miss Pui-Ching Lee, Biostatistics Task Force, Taipei Veteran General Hospital, for assistance with biostatistics analysis; and Miss Sheng-Hung Lee, Division of Endocrine and Metabolism, Taipei Veteran General Hospital, for studying autonomic function of these patients.

References (43)

  • J. Gerritsen et al.

    Impaired autonomic function is associated with increased mortality, especially in subjects with diabetes, hypertension, or a history of cardiovascular disease: the Hoorn Study

    Diabetes Care

    (2001)
  • D.A. Greene et al.

    Are disturbances of sorbitol, phosphoinositide, and Na+-K+-ATPase regulation involved in pathogenesis of diabetic neuropathy?

    Diabetes

    (1988)
  • M. Brownlee

    Glycation products and the pathogenesis of diabetic complications

    Diabetes Care

    (1992)
  • P.A. Low et al.

    The roles of oxidative stress and antioxidant treatment in experimental diabetic neuropathy

    Diabetes

    (1997)
  • A.I. Vinik et al.

    Diabetic autonomic neuropathy

    Diabetes Care

    (2003)
  • P. Gaede et al.

    Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes

    N. Engl. J. Med.

    (2003)
  • D.J. Ewing et al.

    The value of cardiovascular autonomic function tests: 10 years experience in diabetes

    Diabetes Care

    (1985)
  • L.T. Ho et al.

    Reflex heart rate response in normal and diabetic subjects: relationship to age and skin microvascular reflexes

  • K.T. Tang et al.

    Reflex heart rate response in normal Chinese adults: its relationship to age

    J. Formosan Med. Assoc.

    (1987)
  • L.T. Ho et al.

    The diagnostic criteria of diabetic autonomic neuropathy

    Proc. Natl. Sci. Counc. ROC(A)

    (1982)
  • H.C. Bazett

    An analysis of the time-relations of electrocardiograms

    Heart

    (1920)
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