CC BY-NC-ND
0The Egyptian Heart Journal (2014) 66, 63-69
Egyptian Society of Cardiology The Egyptian Heart Journal
www.elsevier.com/locate/ehj www.sciencedirect.com
ORIGINAL ARTICLE
Assessment of cardiac autonomic neuropathy in long standing type 2 diabetic women
CrossMark
Wael Refaie
Cardiology Department, Mansoura Faculty of Medicine, Egypt
Received 2 December 2012; accepted 12 June 2013 Available online 24 July 2013
KEYWORDS
Cardiac autonomic neuropathy;
Heart rate variability; Postural hypotension
Abstract Background: Patients with long standing DM undergoing surgical interventions are put under great challenge as they may have cardiovascular and/or cardiac autonomic neuropathy (CAN). CAN is serious, often overlooked and under diagnosed, with possible arrhythmias and silent ischemia that threaten life.
Objectives: Assessment of CAN in long standing type 2 diabetic women undergoing major surgery. Study design: Cross sectional study.
Patients and methods: One hundred and six type 2 diabetic women scheduled for major surgery were assessed by the autonomic function tests. Only one hundred cases completed the study. CAN was assessed by analyzing HR variations during three standard tests (deep breathing, lying to standing and valsalva maneuver). Sympathetic functions were assessed by checking orthostatic hypotension. The CAN score of each patient was analyzed. Continuous 24 hour ECG monitoring (Holter) was done to evaluate ischemia, arrhythmia, QTc and QTd. Transthoracic Doppler echocardiography, stressing on LVH, diastolic and systolic dysfunctions were carried out. Cases were classified as mild (with only one abnormal test) or severe CAN when two or more abnormal function tests were present. Exclusion criteria include any systemic illness that can affect the study results or the autonomic functions, smoking and HTN.
Results: CAN was detected in 70% of the studied cases, and 70% were severe CAN. Postural hypotension was detected in 34% of the studied cases. QTc prolongation and QT dispersion were frequent. ECG and Doppler echocardiography changes of LVH were more prevalent among patients with CAN. Diabetics with CAN were significantly older had longer duration of DM
Abbreviations: CAN, cardiac autonomic neuropathy; LVH, left ventricular hypertrophy; DM, diabetes mellitus; HTN, hypertension; SBP, systolic blood pressure; DBP, diastolic blood pressure; HRV, heart rate variability * Tel.: +20 01006077310. E-mail address: refaie_wael@yahoo.com. Peer review under responsibility of Egyptian Society of Cardiology.
1110-2608 © 2013 Production and hosting by Elsevier B.V. on behalf of Egyptian Society of Cardiology. http://dx.doi.org/10.1016/j.ehj.2013.06.002
and higher HbA1-c, higher pulse pressure, triglyceride, uric acid and urinary albumin excretion rate. They also had significant increased LVM index, diastolic dysfunction and myocardial ischemia. Conclusion: Middle aged women with long standing diabetes are vulnerable to CAN with postural hypotension and prolonged QTc intervals, QT dispersion, and increased LVMI and myocardial ischemia. Identification of CAN is crucial to exercise prevention against hazards of CV insults during stressful situation as surgery.
© 2013 Production and hosting by Elsevier B.V. on behalf of Egyptian Society of Cardiology.
1. Introduction
Autonomic neuropathy, although not rare, is one of the most insidious complications of diabetes mellitus (DM) especially if long standing and poorly controlled. Cardiac autonomic neuropathy (CAN) is often overlooked both in diagnosis and treatment simply because there is no widely accepted single approach to its diagnosis.1 CAN embraces exercise intolerance, intraoperative cardiovascular liability, orthostatic syndromes and silent myocardial ischemia.2-4 These clinical manifestations can result in life threatening outcomes which unquestionably associate the presence of CAN with the increased risk of CV morbidity and mortality in DM.
In the Eurodiab prospective study on type one diabetes mellitus CAN was among the strongest risk markers of future total and CV mortality exceeding the effect of traditional risk factors as age, obesity, hypertension, dyslipidemia, inflammatory and prothrombotic emerging cardiac risk factors..4,5 In a Meta analysis of 12 published studies Vinik et al.6 reported a constant association between CAN and silent myocardial ischemia and in the DIAD study, on type 2 DM CAN was a stronger predictor of silent ischemia and subsequent cardiac
events.
QTc interval and QTd have been considered as a marker of cardiac autonomic dysfunction and have been demonstrated as an independent predictor of CV mortality and all cause mortality risk in type 2 DM patients.4 Combined abnormality in HRV and QT index was a strong predictor of mortality independent of conventional risk factor.8,9
Action to Control Cardiovascular Risk in Diabetes (ACCORD trial) in the presence of CAN at baseline was an independent contributor to the higher CV mortality risk in both the intensive and standard glycemic arm treatment. Individuals with baseline CAN were two times more likely to die compared with individuals without CAN.10,11 A lot of attention has been given to the CV aspect of autonomic dysfunction especially with the view regarding very tight glycemic control with increased mortality. ACCORD trial12 attributed increased mortality to hypoglycemia induced arrhythmias.1
There is no widely accepted single approach to the diagnosis of CAN, however during the 1970s Ewing et al.,13 advised a number of simple bedside tests of short term RR difference to detect CAN including changes in RR with deep breathing, RR response to standing which induces reflex tachycardia followed by bradycardia and Valsalva ratio which evaluates cardiovagal function in response to a standard increase in intrathorathic pressure. HRV is a physiological phenomenon that reflects the influence of autonomic nervous system on the heart work.13 HRV can be defined as the phenomenon of oscillation in the intervals between the consecutive heart beats as well as the oscillation between consecutive instantaneous heart
rates.13b
Orthostatic hypotension with its many troublesome symptoms ranging from light headedness to near syncope that may be associated with poor quality of life with fall in systolic BP p 20 mmHg and P10 mmHg in diastolic BP during 3 minutes of standing and resolving with sitting or lying down is characteristic of CAN.14,15
The clinical symptoms of CAN may be late, however sub-clinical CAN manifest as changes in HRV may be detected within one year of diagnosis of type 2 DM.16
Pop Bussi and coworkers,17 reported that the prevalence of CAN ranges from as low as 2.5% (DCCT) to as high as 90% in long standing DM and should be instituted at diagnosis of type 2 DM and after 5 years of diagnosis of type 1.18 Vinik and Ziegler,19 reported that, the detection of CAN is a must before exposing patients with long standing DM to stressful situation and also before planning exercises. Diabetics must be tested with a cardiac stress test before undergoing an exercise program. Patients with CAN need to rely on their perceived exertion and not heart rate to avoid the hazardous levels of exercise intensity.19
2. Aims
Assessment of cardiac autonomic dysfunction in middle aged women with long standing type 2 DM who are going to be exposed to stress in the form of major surgery.
3. Design
Cross sectional study.
4. Subjects and methods
The studied cases included one hundred and six women. They are known to be diabetics and were under oral hypoglycemic agents (70 cases) and 30 cases were under combined insulin and sulfonylurea. All were receiving metformin 1.7 gm/day. Their age ranged from 40 to 60 years (mean 52.4 ± 3.7 years). The mean duration of DM was 10 ± 2 years ranging from (614 years). BMI ranging from 25.1 to 29.2 (mean 27.1 ± 1.1). They were scheduled for hysterectomies and/or classical repair.
All medications that can affect the result of the autonomic functions (anticholinergic agents, adrenergic antagonists, vaso-constrictive agents) were withhold during and one week preceding the clinical assessment of autonomic functions.
Examinations were undertaken in the morning at least 2 h after a light breakfast and no caffeine was allowed. The patients were asked about symptoms suggestive of autonomic neuropathy, postural hypotension and myocardial ischemia.
Diabetic complications as retinopathy were checked and peripheral neuropathy, and sudomotor neuropathy were
stressed upon. Clinical examination, with stress on heart rate, SBP, DBP, pulse pressure was undertaken, Testing of auto-nomic parasympathetic dysfunction was assessed by HRV testing of Ewing's methodology 198013 (heart rate ECG RR intervals on resting, standing, deep respiration and valsalva).13 Heart rate variability was calculated from the RR interval using short continuous ECG recording. Continuous 24 hours ECG monitoring (Holter) was also used to evaluate ischemia, arrhythmia, QTc intervals QT/ R-R (Bazetts formula) and QTd (the difference between the longest and the shortest R waves). The resting 12 lead ECG was also undertaken to show beside HRV evidence of LVH QRS amplitude >35 ms in peri-cordial leads (Rv 1,2 + Sv 5,6 >35) and/or ischemia. Prolongation of the QTc interval >460 ms, flattening of the T wave and ST segment depression were considered as evidence of HRV and myocardial ischemia.
Testing for sympathetic dysfunction by postural hypotension in supine and after standing for 3 min was undertaken with the standard mercury sphygmomanometer. The measurement in the supine position was taken after at least 15 min of rest and measurement in standing position was taken at the third minute of standing.14
Transthoracic Doppler echocardiography stressing on LVMI Devereux formula = 0.8 x 1.04 x LV mass {(LVIDD + PWTD + IVSTD)3—LVIDD3} + 0.6 g, diastolic dysfunction utilizing the E/A ratio and for systolic dysfunction the EF and fibrous shortening was carried out.
Biochemical studies were undertaken stressing on blood glucose, fasting and post 75 g glucose challenge together with HbA1-c, serum creatinine, plasma cholesterol, triglyceride, serum uric acid and 24 h urine albumin excretion.
The prevalence and the severity of CAN was assessed according to the number of autonomic function tests of Ew-ing's methodology, and the CAN score in each patient was analyzed.13,19
Subclinical CAN cases or mild CAN with only one abnormal function test were compared to severe CAN cases (2 or 3 abnormal autonomic function).
The study protocol was approved by the scientific committee of Mansoura Faculty of Medicine and informed consents were obtained.
4.1. Exclusion criteria
Systemic illness that can affect the study results or the auto-nomic functions as CHF, CAD, arrhythmia, renal, hepatic impairment, HCV infection, severe anemia, thyroid dysfunction, smoking, concomitant treatment with anticholinergic agents, adrenergic antagonists, and vasoconstrictive agents that can affect the results of autonomic function test and patients with BP P 140/90 mmHg on two occasions 2 weeks apart were not included.
5. Statistical analysis
Was performed by using the statistical package for social science program (SPSS) version "16". The qualitative data were presented as frequency and percentages. The quantitative data were examined by using the Kalmogrov-Smirnov test to test for normal distribution of the data and when parametric, expressed as mean and standard deviation. Student t test was
used, to test for difference in normally distributed quantitative data between the two groups. Mann-Whitney-u test was used for comparison between two groups when data are not normally distributed. Significance was considered when P value was less than 0.05.
6. Results
The prevalence of CAN as assessed by signs of autonomic neuropathy including HRV tests E/I ratio (expiration to inspiration) standing to lying flat, valsalva maneuver, was 70% (20 cases with single HRV testing, 26 cases with 3 HRV testing, and 24 cases with moderate CAN where two HRV tests were present).
Postural hypotension was detected in 34% of the studied cases and mean pulse pressure was significantly elevated in diabetics with CAN when compared to those without CAN (P < 0.01).
Prolonged QTc (>460 ms) in 38% of the whole studied cases and 60% of the CAN cases had significantly increased QTd (>10 ms) when compared to the non CAN group as evident by the continuous 24 h ECG Holter monitoring.
Women with DM and CAN were significantly older with a significant longer duration of uncontrolled DM with insignificant differences in BMI.
Urogenital symptoms were significantly evident in the CAN group (P < 0.04) together with peripheral neuritis detected by monofilament with feet dryness (P < 0.01). SBP, DBP and the mean pulse pressure were significantly higher in the CAN group (P < 0.001).
History suggestive of stable angina and/or acute coronary syndrome showed insignificant differences.
Significant higher BG level and HbA1-c in the CAN group was observed with significant hypertriglyceridemia and elevation in uric acid in the CAN group. The urinary albumin excretion in the CAN group was significantly elevated than in the non CAN group (P < 0.01).Comparing the studied parameters in relation to the severity of CAN showed insignificant changes apart from significant older age, more postural hypotension, HbA1-c, serum creatinine, urine albumin excretion and QTc. Signs of LVH and QTd revealed a borderline significant increase in severe CAN cases.
7. Discussion
It was aimed in the present study to evaluate the CAN in middle aged women with long standing diabetes scheduled for stressful situation in the form of major surgery (hysterectomies and/or classical repair). Detection of CAN preoperatively is necessary as such patients are vulnerable to perioperatve cardiovascular instability with a greater decline in heart rate and BP during induction of anesthesia and more severe
hypothermia.19,3
In the present study, the prevalence of CAN as detected by Ewings et al 1970s proposals of heart rate variability tests (Ew-ings et al. 1980) was high (70%). As the determination of CAN is usually based on a battery of autonomic function tests and as the proceeding from a consensus conference,20 recommended three tests. In the present study, the golden standard clinical autonomic testing21 was followed.
The prevalence of CAN ranged from 20% to 42% according to the way of detecting HRV state being the highest (30%) by the valsalva maneuver procedure and the lowest (20%) by the diminished expiration to inspiration ratio (E/I ratio) and by standing to laying flat. The scoring of CAN was calculated, where more than one fourth (26%) had P 3 positive tests and 24% had P2 positive. This is in accordance with Katsilambo-rus et al.,1 that autonomic neuropathy and CAN are not at all rare, but are often overlooked.
The prevalence of CAN ranged from as low as 2.5% (DCCT)17 to as high as 90% in long standing DM and in 69% of treatment induced neuropathy.22 In the present study the valsalva ratio was 30% and E/I ratio was 20%. Our results are not in accordance with England and coworkers,23 who found that HRV with deep breathing is the most widely used test of cardiovagal parasympathetic dysfunction. Cardiovascular sympathetic function was assessed by measuring the BP response to orthostatic changes24,25 and was detected in 34% of the studied cases.
The prevalence of CAN in the present study is higher than that of Zeigler et al.,26 who by using HRV tests found that 34.3% of type 2 DM patients had abnormal functions. Similar to Cabezas-Cerrato et al.,27 the HR response to deep breathing in the present study was the least evident among the studied cases.
In the present study, the studied cases were all females this could avoid gender related difference in biochemical and hematological values.28,29 CAN was more prevalent in diabetics of longer duration, older age, those with more pulse pressure, higher serum triglycerides and with more elevated
HbA1-c. Kodama et al.,30 in a meta analysis study described the association of pulse pressure as a cardiovascular risk in DM. Makimattila et al.,31 found that poor glycemic control was the most important independent predictor of decrease in all measures of absolute power of HRV.
Our findings are in agreement with those of Voulgari et al.,21 who mentioned that in type 2 DM patients, CAN has been independently associated with elevated BP, hypergly-cemia, longer diabetes duration, dyslipidemia and the presence of microvascular complications.32,21 Katsilambors et al.,1 reported the association of high serum uric acid level and sundo-motor dysfunction in patients with type 2 DM and CAN. In the present study similarly serum uric acid showed higher but insignificant differences (See Table 1).
In the present study (Table 2) the urogenital symptoms were significantly more frequent in diabetics with CAN. This is not in line with Gibons and Freeman33 who reported that symptoms of orthostatic intolerance and gastrointestinal dysfunction, urinary frequency, nocturia and anhydrosis were more frequent in diabetics with CAN.
Peripheral neuropathy was present in 80% of the examined cases. This is in agreement with Vinik and Ziegler,34 and Gandhi et al.,35 who found that combined indices of autonomic and peripheral neurological dysfunction is associated with earlier CAN detection.36,37 In the EURODIAB24 prospective complication study peripheral and autonomic neuropathy were among the strongest risk markers exceeding the effects of the traditional risk factors (See Tables 3-5).
Orthostatic hypotension was demonstrated in 34% of the whole studied cases and in 60% of the CAN group.
Table 1 Prevalence of CAN by the different assessment tests.
Method No of cases Percentage (%)
HRV: flE/I ratio with deep breathing (61.1) 20 20
HRVflStanding to lying flat 20 20
HRV:Valsalva maneuver 30 30
Postural hypotension 34 34
QTc prolongation > 460 mm 38 38
QTd > 10 ms 42 42
Table 2 Clinical findings in diabetes with CAN versus diabetics without CAN.
Present CAN Absent CAN P
No. 70 cases% No. 30 cases%
Age (years) 54.4 ± 6.1 48.6 ± 4.1 <0.001
BMl(Kg/m2) 26.3 ± 1.2 26 ± 1.1 0.226
Duration of DM 9.9 ± 3.1 6.3 ± 1.1 <0.001
Resting heart rate 94 ± 8 92 ± 6 0.172
Postural hypotension 34cases 48.57% 2 cases 6.66% <0.001
Symptoms suggestive of CAN in other systems
-gastrointestinal 4 cases 7.1% 1 case 3.3% 0.88
-Urogenital 20 cases 28.6% 3 cases 10% 0.044
-Sudomotor (dry feet) 8 cases 11.4% 3 cases 10% 0.84
Peripheral neuritis 56 cases 80% 6 cases 20% <0.001
Dry skin 42 cases 60% 3 cases 10% <0.001
SBP 130 ± 5 120 ± 5 <0.001
DBP 80 ± 4 75 ± 5 <0.001
Mean pulse pressure 50.5 ± 3 45.5 ± 2 <0.001
Angina 0 0 1
Orthostatic symptomatology as light headedness, dizziness, fatigability, faintness on standing was very frequent (60%). However no reported cases of clear or near syncope were reported. Orthostatic hypotension in CAN is secondary to efferent sympathetic vasomotor denervation causing reduced vasoconstriction of the splanchinic and other peripheral bed.20 In the present study the resting heart rate in the CAN group was around 100 bpm but was insignificantly rapid than in the
non CAN group. This is in line with Pop-Bussi17 who stated that increased resting heart rate is not a reliable diagnostic criterion for CAN in the absence of other signs.
In the present study QTc prolongation and the more prevalent QT dispersion, are in agreement with Voulgari et al.4 QTc interval was considered as a marker of cardiac autonomic dysfunction and is significantly associated with LVH.4 The increase in the number of the abnormal CAN function tests
Table 3 Biochemical findings in Diabetes with CAN versus diabetics without CAN.
Present CAN Absent CAN P
No. 70 cases No. 30 cases
FBG mgm/dl 180 ± 10 138.6 ± 4.1 <0.001
Post 75 gm glucose challenge mgm/dl 310 ± 9 260 ± 1.1 <0.001
HbA1-c% 10.2 ± 1.1 9.2 ± 1.1 <0.001
S. cholesterol mgm/dl 198 ± 16 193 ± 30 0.39
S. Triglyceride mgm/dl 189 ± 11 180 ± 8.0 <0.001
S. Uric acid mgm% 6.9 ± 1.2 6.1 ± 1.9 0.035
S. Creatinine mgm 1.3 ± 0.2 1.2 ± 0.3 0.097
Urine 24 h alb excretion mg/24 h 130 ± 1.2 105 ± 1.1 <0.001
HB gm% 10.9 ± 0.2 10.8 ± 0.3 0.097
S. TSH 1.8 ± 0.4 1.7 ± 0.5 0.334
Table 4 ECG findings and transthoracic Doppler Echocardiography in Diabetes with CAN versus diabetics without CAN.
Present CAN Absent CAN P
No. 70 cases% No. 30 cases%
QTc interval p 460 ms 42 cases 60% 10 cases 33.3% 0.01
QTd p 10 ms 42 cases 60% 10 cases 33.3% 0.01
Flattened T wave 28 cases 40% 10 cases 33.3% 0.531
ST segment depression 28 cases 40% 9 cases 30% 0.344
Evidence of LVH 28 cases 40% 3 cases 10% 0.003
LVM index p 126 gm/ m2 50 cases 70.1% 10 cases 33.3% <0.001
E/A ratio < 1 40 cases 57.1% 10 cases 33.3% 0.029
EF > 60% 60 cases 85.7% 26 cases 86.6% 0.599
Table 5 Clinical, biochemical and ECG findings of cases with subclinical mild CAN versus severe CAN cases.
Mild CAN 18 cases Moderate to severe CAN 52 cases P
Age (years) 56.9 ± 2.1 55.1 ± 2.5 0.003
BMl(Kg/ m2) 26.6 ± 1.2 27.2 ± 1.1 0.066
WC 95 ± 3.5 96 ± 4.1 0.321
Duration Of DM 9.8 ± 3.1 9.9 ± 1.1 0.893
SBP 138 ± 5 140 ± 5 0.148
DBP 88 ± 4 90 ± 5 0.091
Mean pulse pressure 74.5 ± 4 75.5 ± 3 0.335
Resting Heart Rate 96 ± 8 99 ± 6 0.149
Postural hypotension 2cases 11.1% 32 cases 64% <0.001
HbA1-c 8.9 ± 1.1 10.3 ± 1.1 <0.001
S. cholesterol mgm/dl 205 ± 10.2 210 ± 8.9 0.068
S. Triglyceride mgm/dl 199 ± 8.1 201 ± 7.1 0.355
S. Uric acid mgm % 6.6 ± 1.2 7.1 ± 2.2 0.233
S. Creatinine mgm 1.2 ± 0.2 1.6 ± 0.8 0.001
Urine 24 h alb excretion 190 ± 1.2 200 ± 1.2 <0.001
QTc interval 448.1 ± 9.9 460.1 ± 10.1 <0.001
QTd > 10 ms 6 cases 33.3% 30 cases 57.7% 0.076
Twave - duration 1.6 ± 0.1 1.5 ± 0.8 0.38
-Amplitude 2.9 ± 0.5 3 ± 0.11 0.402
Evidence of LVH 6 cases 33.3% 30 cases 57.7% 0.076
increases the risk more.38 Pappachen et al.39 concluded that QTc interval can be used to diagnose CAN and the combined abnormality of HRV and QT index was a strong predictor of mortality independent of conventional risk factors.40,41
Prolongation of QTc interval was detected in 60% of the CAN cases with elevation of R wave amplitude with decreased HRV. This coincides with the finding of Lombardi.42 LVH was significantly manifest in the CAN group in comparison to the non CAN group.
In the present study QTc interval prolongation (>440 ms) has been associated with increased age, SBP, DBP, central obesity and severity of autonomic neuropathy. This is in accordance with the finding of Ewing et al.43 and Veglio et al.44 Comparing mild CAN cases and severe CAN cases revealed some clinical, biochemical, electrocardiographic and echocar-diographic significant differences including; older age, more postural hypotension, elevated HbA1-c, serum creatinine, 24 h urine albumin excretion and more frequent QTc prolongation which may impose more cardiovascular risk.
8. Conclusion
CAN in women with type 2 DM are common. Detection of CAN irrespective of its scoring in patient with DM is of importance and can help to exercise more precautions during their diabetic management. Special clinics for cardiac autonomic neuropathy may be warranted.
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