Introduction
Diabetic peripheral neuropathy (DPN) is the most prevalent neuropathy in diabetes and a common cause of morbidity. It leads to foot ulceration and predisposes to limb loss, as almost 28% of all foot ulcers ultimately require some form of lower extremity amputation [
1]. Among patients with diabetes mellitus (DM) cardiovascular mortality accounts 43.6% of all deaths [
2].
Diabetes is a pivotal cause of asymptomatic myocardial ischemia (MI) even in the absence of coronary artery disease [
3]. Therefore, early identification of patients with DM at high risk for asymptomatic MI consists of a significant challenge. Evidence suggests an association between cardiovascular autonomic neuropathy (CAN) and an increase in overall mortality or silent myocardial ischemia [
4,
5]. Although DPN has recently been shown to be associated with incident cardiovascular events [
6,
7], the relationship between DPN and MI has never been established.
We hypothesized that DPN may be associated with MI in patients with type 2 DM (T2DM) and no history of cardiovascular events. This association could provide additional information on the link between the risk of cardiovascular disease (CVD) and T2DM, and be useful to better identify patients at risk of MI.
Results
Patient characteristics and between-groups comparisons are presented in Table
1. Patients with DPN had a higher risk of abnormal SSS (OR = 7.99, 95% CI 2.4–26.5), ischemia (OR = 4.25, 95% CI 1.4–12.9), and abnormal RR ratio (OR = 4.15, 95% CI 1.34–12.87). Moreover, abnormal RR ratio and ischemia were significantly higher in patients with DPN and ulcers than in patients with DPN without ulcers or in patients without DPN (Table
1).
Table 1
Participant characteristics and post hoc analysis among groups
Sex (male), n (%) | 17 (41) | 16 (61) | 8 (53) | 0.27 |
Age (years) | 62.5 ± 9.8 | 68 ± 9 | 65.5 ± 10 | 0.08 |
Diabetes duration (years) | 10 (6–12) | 20 (11–28)* | 16 (12–23)* | <0.001 |
HbA1c (%) | 6.9 (6.2–7.5) | 7.1 (6.6–7.6) | 7.2 (6.9–7.9) | 0.13 |
HbA1c (mmol/mol) | 51.9 (44.3–57.4) | 54.1 (48.6–59.6) | 55.2 (51.9–62.8) | 0.13 |
BMI (kg/m2) | 31.2 (28.0–34.0) | 31.0 (27.6–34.1) | 34.9 (28.8–38.9) | 0.32 |
Waist circumference (cm) | 107 ± 12 | 108 ± 12 | 112 ± 9 | 0.31 |
TC (mg/dL) | 177 (154–210) | 179 (154–218) | 169 (152–202) | 0.76 |
TG (mg/dL) | 133 (100–163) | 125 (102–168) | 113 (87–178) | 0.72 |
HDL (mg/dL) | 45 (41–52) | 48 (42–51) | 41 (36–50) | 0.27 |
LDL (mg/dL) | 103 (83–126) | 104 (86–122) | 101 (73–132) | 0.94 |
Smoking, n (%) | 7 (14) | 5 (19) | 4 (27) | 0.72 |
GFR (mL/min/1.73 m2) | 96 ± 32 | 96 ± 29 | 106 ± 30 | 0.56 |
ABI | 1.00 (1.00–1.00) | 1.00 (0.93–1.00) | 1.00 (0.97–1.18) | 0.15 |
NDS | 0 (0–2) | 8 (6–10)* | 12 (10–14)*§
| <0.001 |
Abnormal RR ratio, n (%) | 5 (12.1) | 5 (19.2) | 10 (66.7)*§
| <0.001 |
Ischemia, n (%) | 3 (7.3) | 7 (26.9)* | 9 (60)*§
| <0.001 |
Abnormal SSS, n (%) | 4 (9.8) | 10 (38.5)* | 9 (60)* | <0.001 |
Univariate and multivariate regressions identified NDS, waist circumference and gender as significant predictors of SSS (adjusted
R
2 = 0.22), with NDS being the most strongly related (
β = 0.32,
p = 0.003) (Table
2). Sensitivity analyses removing patients with abnormal RR ratio or without ulcers yielded to similar results, with NDS significantly associated with SSS (
β = 0.32,
p = 0.003 and
β = 0.24,
p = 0.04, respectively) (supplementary Table S1). The AUC of the ROC curve was 0.76 (95% CI, 0.65–0.86;
p < 0.001). The cutoff point of the NDS for which sensitivity and specificity are optimal was 5, i.e. the threshold value that is commonly accepted as indicative of DPN.
Table 2
Regression analyses predicting the Summed Stress Score (SSS)
NDS | 0.38 | <0.001 | 0.32 | 0.003 |
Waist circumference | 0.19 | 0.089 | 0.22 | 0.03 |
Age | 0.31 | 0.004 | 0.09 | 0.13 |
Sex (male) | −0.42 | <0.001 | −0.24 | 0.02 |
LDL | −0.17 | 0.12 | −0.04 | 0.67 |
Duration of diabetes | 0.12 | 0.28 | – | – |
HbA1c | 0.14 | 0.21 | – | – |
ABI | −0.08 | 0.46 | – | – |
GFR | −0.10 | 0.36 | – | – |
The RR ratio was also significantly associated with SSS in univariate (ρ = −0.30, p = 0.005) and multiple regressions (adjusted R
2 = 0.18, β = 0.24, p = 0.02) (supplementary Table S2). Orthostatic hypotension was diagnosed only in 3 (3.4%) patients with DPN.
Discussion
Large cohort studies have established the relationship between DPN and cardiovascular risk factors [
7] or events [
6]. However, the mechanisms behind this link are still not clear, as recently published endothelial dysfunction occurs early in the pathophysiology of diabetes and could be a potential link between cardiovascular risk factors and DPN [
14]. In the present study, we further show that DPN is strongly associated with asymptomatic MI assessed with Technetium-99 m sestamibi SPECT imaging in T2DM patients who were free of cardiovascular events, independently from other risk factors as was shown in the regression analysis. Moreover, AUC of the ROC curve showed a fair to good performance of the NDS to discriminate patients with ischemia. We would like to point out that, interestingly, the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study did not find any association between peripheral neuropathy and MI using the same technique. This discrepancy might be explained by the use of differing methods of testing and evaluating DPN in our study. The DIAD study used the presence of two or more signs and symptoms of diabetic neuropathy. Although a trend towards higher frequency of DPN was observed among patients with moderate-to-large stress perfusion abnormality, it was not significant [
4]. Using continuous scales (i.e. DPN and SSS) might have provided us with more sensitivity to detect this relationship. Another explanation could be the duration of diabetes as the average duration of diabetes was shorter in the DIAD study (8.1 vs. 14.8 years in our study) [
4], therefore patients were less likely to have developed complications. Considering the importance of diabetes duration as a determinant for DPN and ischemia, we ran a sensitivity analysis including diabetes duration in the model. However, this did not significantly affect the findings.
On the other hand, we found similar results to the DIAD study regarding markers of CAN. Abnormal valsalva ratio was identified as the strongest predictor of ischemia in the DIAD study. In our study, the estimation of autonomic neuropathy was performed with the RR ratio and orthostatic hypotension, as suggested by the European Diabetes (EURODIAB) Prospective Complications Study due to the risk of retinal hemorrhage [
7]. A significant correlation between the RR ratio and MI was observed in the univariate and multivariate analyses. This finding is in compliance with numerous studies stressing an association between CAN in early stages and increased overall mortality or silent myocardial ischemia [
4,
5]. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial suggested the role of CAN as a possible predictor for CVD mortality [
5].
Interestingly, sensitivity analysis after removing patients with abnormal RR ratio did not affect the main finding of our study. This suggests that the association between diabetic neuropathy and MI exceeds autonomic neuropathy. DPN had previously been associated with increased incidence of CVD [
6]. Although the link between these two conditions has not been fully elucidated, they probably share similar pathophysiological pathways. Indeed, DPN, which is traditionally counted among microvascular complications, might be caused by neuronal cells abnormalities, such as oxidative or inflammation stress [
15] that also affect the endothelium.
One limitation of the present study is that we only included 15 patients with ulcers and we did not reach statistical significance when assessing the effect of both DPN (OR = 3.88, 0.97–15.4;
p = 0.054) and ulcers (OR = 3.73, 0.87–161;
p = 0.077) on abnormal SSS, probably because of a lack of power. Although proper sample size calculation could not be done a priori considering that the variables to be included in the multivariate analysis (primary endpoint) were not known, our final sample provided satisfactory power if we consider the rule of thumb of a minimum of 10 participants required per variable included in the model. Additionally, the trend we observed is consistent with the 2.2 increase in relative risk of fatal MI in patients with ulcers [
2] confirming other studies [
16]. This could be partly due to increased chronic inflammation, which is involved in the development of atherosclerosis in these patients [
2]. Yet, removing patients with active ulcers from analysis did not significantly change the main conclusion. Another limitation is that this study is cross-sectional and the absence of follow-up does not allow us to draw definitive conclusions on any causal relationship between factors. Finally, the diagnosis of DPN is observer-dependent and could be prone to subjectivity. In order to decrease the risk of objective bias, the same experienced physician, prior to SPECT imaging, performed the DPN assessments.
Conclusions
In conclusion, the present study indicates that, besides autonomic neuropathy, DPN is strongly associated with asymptomatic MI. This suggests that NDS could be a useful tool to appraise the risk of early cardiovascular complications among diabetic patients, and needs to be further evaluated in larger-scale prospective studies.
Acknowledgments
This study was funded by Papageorgiou General Hospital, Thessaloniki. D. Baltzis received a scholarship from the North Greece Association of Diabetes. M. Roustit received funding from the Fondation AGIR pour les Maladies Chroniques. D. Baltzis collected the data and contributed to writing the manuscript, M. Roustit and M. G. Grammatikopoulou performed the statistical analyses and contributed to writing the manuscript, D. Baltzis, M-C Trakatelli and C. Manes were responsible for the conception and design of the study. I. Iakovou, D. Katsaboukas and V. Athanasiou performed the Technetium-99m Sestamibi SPECT imaging and analyzed the data. A. Veves contributed in data interpretation and manuscript drafting. All authors critically revised the manuscript for important intellectual content and approved the final version of the manuscript. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.
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