Introduction
Diabetes is an increasing health-care problem [
1]. Cardiovascular complications including coronary artery disease (CAD), are the most common causes of mortality and morbidity in patients with type 2 diabetes [
2]. Because patients with type 2 diabetes often suffer from CAD without symptoms, risk stratification is needed to identify patients at high risk of CAD. In the DIAD (detection of silent myocardial ischemia in asymptomatic diabetic subjects) study the overall prevalence by SPECT of silent myocardial ischaemia was 22% [
3]. Although traditional risk factors failed to predict silent myocardial ischaemia, cardiac autonomic neuropathy (CAN) assessed by heart rate variability (HRV), was a strong predictor of silent myocardial ischaemia in this study. Furthermore, CAN is one of the most common complications associated with diabetes and has been associated with an increased risk of mortality and major cardiovascular events [
4]. CAN assessed by HRV is a sensitive method for detecting neuropathy of the vagal nerve, characterized by resting tachycardia and reduced HRV [
5]. In addition, sympathetic cardiac innervation can nowadays be assessed directly and noninvasively with
123I-
mIBG myocardial scintigraphy in many clinical disorders, including diabetes [
6]. Several previous studies have evaluated the relationship between HRV and
123I-
mIBG myocardial scintigraphy in patients with diabetes [
7‐
9]. However, the current observational study specifically evaluated the prevalence of CAN in patients with type 2 diabetes and without symptoms of CAD comparing HRV with
123I-
mIBG myocardial scintigraphy.
Discussion
In the present study, the prevalence of CAN in patients with type 2 diabetes, asymptomatic for CAD and with normal myocardial perfusion, was assessed by HRV and 123I-mIBG scintigraphy; the prevalence of CAN was 27% by HRV and 58% on 123I-mIBG scintigraphy. Importantly, in almost 50% of patients with normal HRV, 123I-mIBG scintigraphy showed CAN, suggesting that 123I-mIBG imaging may be more sensitive for the assessment of CAN than HRV.
CAN is an important complication of diabetes. CAN results from damage to the autonomic nerve fibres innervating the heart and blood vessels, which causes abnormalities in heart rate control and impairs vascular dynamics. Clinical manifestations of CAN include exercise intolerance, intraoperative cardiovascular instability, orthostatic hypotension, asymptomatic ischaemia and painless myocardial infarction [
29]. Furthermore, CAN is associated with poor outcome related to ventricular arrhythmias and sudden cardiac death [
4,
30]. In clinical practice, it is possible to assess CAN by measuring HRV. When CAN has progressed significantly, it may result in a reduction in HRV [
31]. Measuring HRV has been shown to be a simple, noninvasive method to evaluate the sympatheticovagal balance at the sinoatrial level, and can identify patients at risk of cardiac arrhythmias and sudden death [
32,
33].
Therefore, assessing HRV is potentially important in the management of patients with diabetes. In the current study, a series of simple bedside tests for detecting CAN were used [
34]. As early as 1976 Ewing et al. reported the results in 37 diabetic patients with symptoms and clinical features suggestive of autonomic neuropathy who were followed for 33 months [
35]. The authors concluded that simple autonomic function tests provided significant prognostic information, with abnormal tests being associated with a high mortality. These results were confirmed in a larger population of 605 patients (the Hoorn study) with a follow-up period of 9 years [
4]. Mortality during the follow-up was 17% (101 patients); patients with diabetes and impaired autonomic function had a twofold mortality risk.
123I-
mIBG is an analogue of the false neurotransmitter guanethidine. It is taken up by adrenergic neurons in a similar fashion to norepinephrine and does not undergo intracellular metabolism. Imaging with this agent reflects uptake in presynaptic neurons as modulated by the norepinephrine transporter and the status of intraneuronal storage of norepinephrine [
36]. Recently, Nagamachi et al. investigated retrospectively the long-term (mean 7.2 ± 3.2 years) prognostic value of
123I-
mIBG scintigraphy for both cardiac events and mortality in 144 patients with type 2 diabetes and normal myocardial perfusion [
6]. A decreased delayed HMR was an independent predictor of long-term mortality. A combination of
123I-
mIBG scintigraphy parameters and HRV was independently predictive of cardiac events.
Previous data have suggested that
123I-
mIBG scintigraphy may be more sensitive than HRV for the detection of CAN in diabetic subjects [
16,
37]. The role of CAN in asymptomatic diabetic patients has been described by Valensi et al. [
38]. In that study, 75 patients with at least two cardiovascular risk factors, were evaluated for silent myocardial ischaemia and CAN with a follow-up period of 3–7 years. Of these patients, 11 (15%) had a major cardiovascular event, and multivariate analysis demonstrated that CAN was a better predictor of major cardiac events than silent myocardial ischaemia. Furthermore, Langer et al. investigated CAN in relation to HRV and
123I-
mIBG scintigraphy in 23 normal subjects and 65 asymptomatic patients with diabetes type 2 and silent myocardial ischaemia [
39]. The authors found that
123I-
mIBG uptake was largely diminished in diabetic patients, especially in those with clinically detectable CAN; moreover, diffuse abnormalities in
123I-
mIBG uptake were observed in patients with silent myocardial ischaemia.
In the present study, we performed a systematic, head-to-head comparison between HRV and
123I-
mIBG scintigraphy in 88 patients with type 2 diabetes asymptomatic for CAD to evaluate the presence of CAN. We included many more patients than previous studies, but although the inclusion criteria were different, our results are in line with those of previous studies showing that
123I-
mIBG scintigraphy identified a significantly higher proportion of patients with CAN than HRV [
16,
40,
41]. The fact that more patients exhibit abnormalities in
123I-
mIBG imaging as compared to HRV underscores the suggestion that abnormalities in cardiac sympathetic innervation occur prior to ECG-based (HRV) cardiac autonomic dysfunction [
16]. An alternative explanation is that
123I-
mIBG scintigraphy mainly reflects sympathetic innervation, whereas HRV may be more related to parasympathetic function [
42]. It remains to be determined which of these two parameters is more useful in predicting long-term outcome.
While HRV and other traditional parameters provide an impression of global innervation abnormalities,
123I-
mIBG scintigraphy with SPECT provides information on regional innervation. The findings of the current study indicate that regional abnormalities occur often in patients with asymptomatic diabetes. Other studies using
123I-
mIBG scintigraphy in populations with various cardiovascular diseases have also shown regional innervation abnormalities [
16,
40,
41,
43]. For example, Langer et al. evaluated 65 diabetic patients and noted significantly impaired
123I-
mIBG uptake in the inferior wall and apex [
39]. Additional studies have shown that abnormalities in CAN tend to occur first in the inferior regions of the myocardium and then progressively spread to adjacent segments [
44,
45].
Clinical implications
Of all established diabetes-related and cardiac risk factors in patients with asymptomatic diabetes, poor glycaemic control is of great importance in the development and progression of CAN [
37,
44]. Accordingly, early detection of CAN is of the utmost importance. As observed in the current study,
123I-
mIBG scintigraphy appears more sensitive than HRV for the detection of CAN in asymptomatic diabetic patients without myocardial perfusion abnormalities. Identification of these patients may permit risk factor modification and intensive medical treatment aiming at better glycaemic control, which in turn may favourably affect outcome [
46‐
49]. Indeed, several studies have shown that improvement in CAN (as evidenced by HRV) can be achieved by weight loss and regular exercise [
50,
51]. Furthermore, progression of CAN can also be delayed by intensive medical therapy, thereby reducing the risk of premature mortality [
52].
Limitations
The current study included only diabetic patients, and no control population was available. Precise threshold values for diabetic patients and normal controls need to be further explored for the individual 123I-mIBG variables (HMR, WR and TDS) to define CAN, and these cut-off values may be dependent on patient demographics and acquisition. Moreover, the variation in the individual values appears to be substantial and the use of a composite endpoint to define an abnormal 123I-mIBG study may be preferred.
Conclusion
The poor long-term prognosis in asymptomatic diabetic patients with CAN justifies early risk stratification. In the current head-to-head comparison between 123I-mIBG scintigraphy and HRV, 123I-mIBG scintigraphy identified significantly more patients with CAN than HRV. These findings suggest that 123I-mIBG myocardial scintigraphy may be suited to early detection of CAN. However, the current limitations in defining imaging abnormalities in diabetic patients need to be considered and more data are clearly needed.