A well-established, comprehensive, and simple test battery was used here to re-evaluate risk factors for cardiovascular autonomic neuropathy (CAN) in type 2 diabetes. One hundred and seventy-four patients with type 2 diabetes were evaluated through the methods of deep breathing and Valsalva maneuver for correlation with factors that might influence the presence and severity of CAN. The Composite Autonomic Scoring Scale (CASS) was used to grade the severity of autonomic impairment, and CAN was defined as a CASS score ≥2. Results showed that nephropathy, duration of diabetes, blood pressure, uric acid, and the presence of retinopathy and metabolic syndrome significantly correlated with the CASS score. Age may not be a risk factor for diabetic CAN. However, the effects of diabetes on CAN are more prominent in younger patients than in older ones. Diabetic retinopathy is the most significant risk factor predictive of the presence of CAN in patients with type 2 diabetes.
Cardiovascular autonomic neuropathy (CAN) is one of the most clinically relevant complications of diabetes. The risk of developing CAN in diabetes depends on several factors, the most intuitive and most well-established of which is chronic hyperglycemia, including the duration and glucose level. Old age, nephropathy, and vascular risk factors such as hypertension and dyslipidemia have also been associated with increased severity of CAN [
The prevalence of CAN among patients with diabetes varies widely in different reports, perhaps due to different patient groups (different ages and different durations of diabetes), different tests used, and different diagnostic criteria [
The present study evaluated cardiovascular autonomic functions, including both cardiovagal and adrenergic functions, by using simple, time-saving, and well-established methods. Factors that might influence the presence and severity of CAN in patients with type 2 diabetes were also assessed. Lastly, the association between these risk factors and CAN was re-evaluated. The successful translation of these approaches to the clinics enables not only the prediction of outcome but also the assessment of the impact of factors on the therapeutic efficacy of patients with diabetes.
This cross-sectional study evaluated 174 patients with type 2 diabetes from the outpatient diabetes clinic at Kaohsiung Chang Gung Memorial Hospital between April 2011 and July 2011.
Patients were excluded if they had the following: (1) suffered from moderate-to-severe heart failure (NYHA class III and IV); (2) had any type of arrhythmia that prevented the analysis of heart rate variability, or pacemaker implantation due to any cause; (3) had neoplastic disorders; (4) had degenerative disorders known to affect the autonomic system, such as Parkinson’s disease, diffuse Lewy-body disease, multiple system atrophy, and pure autonomic failure; or (5) had a history of major stroke (brain stem or large hemispherical lesions).
The hospital’s Institutional Review Committee on Human Research approved the study protocol, and all of the study subjects provided informed consent.
Each patient participated in a detailed interview regarding their personal disease and a physical examination that included measurements of height, weight, and waist circumference. All of the subjects then underwent an autonomic survey, including deep breathing and Valsalva maneuver (VM) tests, as described by Low [
Heart rate (HR) was derived from continuously recorded standard three-lead ECG (Ivy Biomedical, model 3000; Branford, CT). Arterial BP was continuously measured at the finger by using beat-to-beat photoplethysmographic recordings (Finometer Pro, Ohmeda; Englewood, OH). Parameters of HR response to deep breathing (HR_DB) and Valsalva ratio (VR) were obtained through tests computed by Testworks (WR Medical Electronics Company, Stillwater, MN). To quantify the degree of dysfunction, the measures of HR_DB and VR were transformed into normal deviates (NDs) by using the Neuropcentiles software (WR Medical Electronics Company) [
The severity of CAN was assessed by using the cardiovagal and adrenergic subscores of the Composite Autonomic Scoring Scale (CASS) [
Modified Composite Autonomic Scoring Scale (subscores in cardiovagal and adrenergic domains).
Cardiovagal | |
---|---|
0 | Normal |
1 | HR_DB mildly reduced but >50% of minimum |
2 | HR_DB reduced to <50% of minimum or HR_DB + VR reduced |
3 | Both HR_DB and VR reduced to <50% of minimum |
|
|
Adrenergic | |
|
|
0 | Normal |
1 | Early phase II reduction >20 but <40 mmHg MBP (30–40 if >50 years) |
Late phase II does not return to baseline | |
Pulse pressure reduction to ≤50% of baseline | |
2 | Early phase II reduction >40 mmHg MBP |
3 | Early phase II reduction >40 mmHg + absent late phase II and phase IV |
HR_DB: heart rate response to deep breathing; VR: Valsalva ratio; MBP: mean blood pressure.
The parameters evaluated were age, duration of diabetes, microvascular complications of diabetes (retinopathy and nephropathy), diabetic control (glycohemoglobin, HbA1c), associated medication (i.e., insulin, diuretics, beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers [ACEI/ARB], and calcium channel blockers [CCB]), inflammatory condition (hsCRP), body mass index (BMI), waist circumference, and biochemical data, including total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), uric acid, serum creatinine, and estimated glomerular filtration rate (GFR), which was calculated by using the modified Diet and Renal Disease equation. Albuminuria was determined by measuring the urinary albumin-to-creatinine ratio (UACR) in a spot urine test.
Retinopathy was determined through fundus photography by an experienced ophthalmologist (J.-J. Lee) who was blinded to the autonomic test results. Diabetic retinopathy (DR) was classified as one of the following three stages: stage 0: no apparent retinopathy (equivalent to the scale of Early Treatment of Diabetic Retinopathy Study [ETDRS] level 10); stage 1: nonproliferative diabetic retinopathy (NPDR; ETDRS level 20–55); and stage 2: proliferative diabetic retinopathy (PDR, ETDRS level >61) [
Moreover, hypertension was defined as a systolic BP > 140 mmHg and/or a diastolic BP > 90 mmHg, or being under antihypertensive treatment. Metabolic syndrome was defined as meeting at least two of the following criteria: (1) waist circumference >90 cm for men and >80 cm for women, (2) serum triglyceride level ≥150 mg/dL or being under drug treatment for elevated triglycerides, (3) serum HDL-C level <40 mg/dL in men and <50 mg/dL in women, or being under drug treatment for low HDL-C, and (4) elevated BP (systolic BP ≥ 130 mmHg and/or diastolic BP ≥ 85 mmHg, or a previous diagnosis of hypertension).
Data are expressed as mean
Of the 174 (117 men, 57 women) patients diagnosed with type 2 diabetes, 56 were administered insulin therapy. Their demographic characteristics and biochemical and autonomic parameters are listed in Table
Characteristics and biochemical data of patients with type 2 diabetes.
Characteristics | Mean ± SD [median (IQR)] |
---|---|
Age (year) | 63.8 ± 9.2 |
Male/female | 117/57 |
Body weight (kg) | 69.8 ± 12.2 |
Body height (cm) | 162.4 ± 8.0 |
Body mass index (kg/m2) | 26.2 ± 3.7 |
Waist circumstance (cm) | 93.2 ± 10.6 |
Duration of diabetes (year) | 11.9 ± 7.0 |
|
|
HbA1c (mmol/mol) (NGSP, %) | 55 ± 10 (7.2 ± 0.9) |
GFR (mL/min/1.73 m2) | 60.4 ± 29.1 |
UACR (mg/mg) | 0.10 [0.02, 0.38] |
hsCRP (mg/L) | 1.00 [0.44, 2.3] |
UA (mg/dL) | 7.3 ± 2.0 |
Cholesterol (mg/dL) | 153.2 ± 29.5 |
LDL-C (mg/dL) | 74.1 ± 26.3 |
HDL-C (mg/dL) | 52.3 ± 13.6 |
Triglycerides (mg/dL) | 114.0 [80.8, 168.0] |
|
|
SBP (mmHg) | 138.8 ± 19.1 |
DBP (mmHg) | 74.2 ± 10.5 |
|
|
HR_DB (beats/min) | 7.2 ± 4.6 |
VR | 1.29 ± 0.18 |
|
−1.04 ± 1.06 |
|
−1.83 ± 0.78 |
Cardiovagal subscore | 0 |
Adrenergic subscore | 0 |
CASS | 0 |
Histograms of cardiovascular autonomic scores, including cardiovagal and adrenergic subscores, and cardiovascular CASS score of the study patients. CASS: Composite Autonomic Scoring Scale.
Of the 159 patients with a valid CASS score, 41.5% (66/159) had CAN, which was defined as a minimum score of 1 in both the cardiovagal and adrenergic domains or a minimum score of 2 in one domain [
The CAN group was younger (60.7 ± 9.4 versus 64.8 ± 8.3 years,
Demographic data between groups of CAN and non-CAN.
Non-CAN ( |
CAN ( |
|
|
---|---|---|---|
Age (year) | 64.8 ± 8.3 | 60.7 ± 9.4 |
|
Body mass index (kg/m2) | 26.0 ± 3.6 | 26.3 ± 3.8 | 0.524 |
Waist circumstance (cm) | 92.9 ± 10.6 | 92.9 ± 10.8 | 0.815 |
Duration of diabetes (year) | 11.5 ± 6.7 | 12.8 ± 7.5 | 0.331 |
SBP (mmHg) | 137.1 ± 20.1 | 141.0 ± 18.7 | 0.205 |
DBP (mmHg) | 74.4 ± 11.3 | 74.5 ± 10.0 | 0.921 |
HbA1c (mmol/mol) (NGSP, %) | 54 ± 9 (7.1 ± 0.8) | 56 ± 12 (7.3 ± 1.1) | 0.175 |
GFR (mL/min/1.73 m2) | 63.1 ± 26.8 | 58.9 ± 31.9 | 0.120 |
UACR (mg/mg) | 0.05 [0.01, 0.24] | 0.14 [0.05, 0.57] |
|
hsCRP (mg/L) | 0.95 [0.44, 2.02] | 1.05 [0.49, 2.30] | 0.442 |
UA (mg/dL) | 7.1 ± 1.8 | 7.6 ± 2.3 | 0.126 |
Cholesterol (mg/dL) | 151.3 ± 32.8 | 155.7 ± 25.0 | 0.115 |
LDL-C (mg/dL) | 72.7 ± 28.9 | 76.3 ± 23.8 | 0.112 |
HDL-C (mg/dL) | 51.8 ± 12.6 | 54.7 ± 14.8 | 0.222 |
Triglycerides (mg/dL) | 135.0 ± 85.0 | 123.5 ± 70.0 | 0.600 |
|
|||
Sex (F/M) | 26/67 | 24/42 | 0.263 |
Insulin | 24/93 | 27/66 |
|
ARB/ACEI | 72/93 | 54/66 | 0.678 |
Beta-blocker | 24/93 | 27/66 | 0.055 |
CCB | 34/93 | 29/66 | 0.410 |
Diuretics | 46/93 | 44/66 |
|
Metabolic syndrome | 66/93 | 55/66 | 0.059 |
Retinopathy† |
|
HbA1c: glycohemoglobin; GFR: glomerular filtration rate; UACR: urinary albumin-to-creatinine ratio; hs-CRP: high-sensitive C-reactive protein; UA: uric acid; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; ARB: angiotensin receptor blocker; ACEI: angiotensin-converting-enzyme inhibitor; CCB: calcium-channel blocker.
†Retinopathy was categorized into stages 0, 1, and 2.
Statistical analysis of the differences between clinical manifestations and laboratory data between the two patient groups revealed significant findings for the following parameters: age (
Logistic regression analyses of risk factors for cardiovascular autonomic neuropathy.
Adjusted OR of CAN (95% CI) |
|
|
---|---|---|
Age | 0.95 (0.90–0.99) |
|
UACR | 1.24 (0.66–2.33) | 0.504 |
Retinopathy | ||
Stage 1 | 2.73 (1.14–6.54) |
|
Stage 2 | 11.19 (4.15–30.16) |
|
OR: odds ratio; CAN: cardiovascular autonomic neuropathy; CI: confidence interval; UACR: urinary albumin-to-creatinine ratio.
An analysis of the association between risk factors and individual autonomic parameters and scores (Table
Univariate correlation analysis between individual risk factors and autonomic parameters/scores.
|
|
Cardiovagal subscore | Adrenergic subscore | CASS | |
---|---|---|---|---|---|
Age |
|
0.004 |
|
0.158 |
|
Body mass index | −0.107 | −0.079 | 0.096 | 0.003 | 0.085 |
Waist circumstance | −0.071 | −0.049 | 0.056 | −0.077 | 0.029 |
Duration of diabetes | −0.017 |
|
0.023 | 0.154 | 0.077 |
HbA1c | −0.089 | −0.077 | 0.145 | −0.022 | 0.069 |
SBP | −0.020 |
|
0.051 | 0.148 | 0.081 |
DBP | 0.007 | −0.113 | −0.039 | 0.013 | −0.050 |
GFR | 0.086 |
|
−0.048 |
|
−0.153 |
UACR |
|
|
|
|
|
hsCRP | −0.088 | −0.153 | 0.093 | 0.106 | 0.102 |
UA | −0.090 | −0.139 | 0.111 |
|
|
Cholesterol | −0.117 | −0.078 | 0.122 | 0.028 | 0.073 |
LDL | −0.109 | −0.063 | 0.111 | 0.045 | 0.092 |
HDL | −0.028 | 0.025 | 0.035 | 0.022 | 0.022 |
Triglycerides | 0.029 | −0.146 | 0.011 | 0.042 | 0.024 |
|
|||||
Retinopathy† |
|
|
|
|
|
Metabolic syndrome | −0.095 |
|
|
|
|
HbA1c: glycohemoglobin; SBP: systolic blood pressure; DBP: diastolic blood pressure; GFR: glomerular filtration rate; UACR: urinary albumin-to-creatinine ratio; hs-CRP: high-sensitive C-reactive protein; UA: uric acid; LDL: low-density lipoprotein; HDL: high-density lipoprotein.
†Retinopathy is categorized into stages 0, 1, and 2.
Although cardiovascular autonomic reflex tests [
The prevalence of CAN in the study patients was 41.5% (66/159). Among them, 44 (66.7%) had a CASS score of 2 or 3. The prevalence of CAN in previous reports varied widely from 2.5 to 50% [
Surprisingly, the CAN group was younger than the non-CAN group. There were strongly significant correlations between age and
According to our data, DR is a strong predictor for CAN. The importance of such a finding has not been sufficiently stressed although the correlation between CAN and retinopathy has been mentioned in some reports [
The correlation between nephropathy and CAN has been reported in several studies [
Vascular risk factors such as hypertension and dyslipidemia have been associated with CAN. The data here shows that systolic BP significantly correlates with
The effects of UA on autonomic function or cardiovascular function remain controversial [
This study has some limitations. First, the prevalence of CAN in such patients cannot reflect the real conditions of general patients with diabetes. Patients with better compliance tend to be recruited in studies; hence, these patients have relatively good serum glucose control. The HbA1c value of the patients in this study was 7.2 ± 0.9. This narrow HbA1c spectrum may explain why statistical analyses fail to show any significant correlation between HbA1c and autonomic parameters. Furthermore, the medication effects on autonomic function tests were not eliminated in this study. Beta-blockers, CCBs, and diuretics are likely to influence the autonomic test results. Due to ethical considerations, these drugs were not stopped before the tests. Fortunately, the effects did not seem to be obvious and there was only a borderline significant difference in diuretic use between the CAN and non-CAN groups.
In conclusion, retinopathy is the most significant risk factor in predicting the presence of CAN in patients with type 2 diabetes. Old age may not be a risk factor for diabetic CAN. On the contrary, the effects of diabetes on CAN are more prominent in younger patients than in older ones.
The authors declare that there is no conflict of interests regarding the publication of this paper.
Drs. Cheng-Hsien Lu and Rue-Tsuan Liu contributed equally to this work.