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Cardiac Autonomic Neuropathy in Type 2 Diabetes:
Predicting Cardiac Risk
Margaret M. McCarthy1 Lawrence Young2 Silvio Inzucchi2
Janice Davey2 Frans J Th Wackers2 Deborah A. Chyun1
1New York University College of Nursing2Yale University School of Medicine
Council for the Advancement of Nursing Science
September 13, 2012
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Background
• Individuals with diabetes mellitus (DM) at increased risk of morbidity and mortality associated with coronary artery disease (CAD)
• One quarter have clinically unrecognized disease
• Asymptomatic nature presents unique challenges in primary/secondary prevention as routine screening not advocated
• Current risk calculators have not performed well– Not account for gender difference and glycemic
status
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Background (2)
• Knowledge of additional risk factors, particularly those related to long-term glucose control might assist in identifying high-risk patients
• Cardiac autonomic neuropathy (CAN) hypothesized to contribute to silent ischemia and adverse outcomes– Underutilized in the clinical setting– Possible role in identifying high-risk– Need to capture DM-specific predictors
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Purpose
• Determine the association of CAN measures with CAD events (cardiac death, acute coronary syndromes, heart failure, and revascularization)
• Examine gender differences in relation to CAD events
• Identify sociodemographic, T2DM-related and CAD risk factors associated with CAN
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Methods
• Secondary analysis of data from a multi-site trial, the
Detection of Ischemia in Asymptomatic Diabetics (DIAD) Study
• Randomized screening trial
• Silent ischemia
• Prevalence
• Predictors
• 5 year outcomes of events
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Subjects and Setting
• Men and women (N=1119) • Age 50 to 75 • History of T2DM• No previous diagnosis of CAD• Followed over 5 years from 14 sites across the
United States and Canada• Follow-up phone calls every 6 months• All CAD events adjudicated
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Measures
• Baseline assessment
• Sociodemographic
• Diabetes-related
• Cardiac risk factors
• Testing for CAN
• Cardiac events collected every 6 months
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Measures of CAN
• Assessed using standard heart rate (HR) and
blood pressure (BP) based Ewing tests
– HR during deep breathing (HRDB):6 breaths/ min
– Valsalva ratio (VR):forced expiration at 40mmHg
– Standing HR (R30:15):15th and 30th beats
– Standing BP and handgrip BP obtained
• Power Spectral Analysis (PSA) Heart Rate
Variability (HRV)
– Low (LF) and high frequency (HF); LF:HF
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Data Analysis
• SAS 9.2
• Spearman Correlation
• Chi-square and t-tests
• Logistic Regression
• Cox Proportional Hazards
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Results
• Subject characteristics
• Cardiac events over 5 years
• Factors associated with and predictive of
cardiac events
• Measures of CAN
• Gender differences
• Clinical factors predictive of CAN
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Subject Characteristics
• Mean age: 61 ± 6.6 years
• Women: 46% (n=519)
• Race/ethnicity: 17% (n=190) Black
• T2DM duration: 8.5 ± 7.0 years
• HbA1c: 7.1 ± 1.5 %
• Insulin use: 23% (n=260)
• Resting heart rate (beats/min): 70 ± 10
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Cardiac Events over 5 Years
• 8.4% (n=94) had cardiac events
• Cardiac death
• Acute coronary syndrome
• Heart failure
• Revascularization
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Factor No Event(n=1,025)
Event(n=94)
P-value
HRDB 1.15±.11 1.14±.13 .96
VR 1.56±.27 1.41±.13 .0004
R30:15 1.24±.15 1.19±.11 .08
BP-stand 1.2±15 5.6±14 .007
BP-HG 18.3±9.4 19.6±10.2 .21
LF 401±548 285±296 .009
HF 195±319 140+198 .06
CAN Measures and Events
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Factor HR 95% CI P-value
Black Race HR=.41 .19-.88 .02
Insulin Use HR=.51 .30-.88 .01
Duration of T2DM HR=1.07 1.04-1.10 <.0001
HbA1c HR=1.26 1.10-1.43 .0007
Peripheral Numbness HR=1.92 1.27-2.92 .002
Predictors of Cardiac Events in All Subjects
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Factor HR 95% CI P-value
Family history CAD HR=1.69 1.06-2.69 .03
Waist-to-Hip Ratio HR=1.04 1.01-1.07 .003
Baseline Physical Inactivity HR=1.52 .99-2.35 .05
Highest Quartile Resting Pulse Pressure
HR=2.17 1.41-3.3 .004
Lowest quartile of VR+ HR=1.59 1.02-2.48 .04
Predictors of Cardiac Events in All Subjects
+Lowest quartile of Valsalva is < 1.37 with Anscore or 1.17 without
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Factors Associated with Cardiac Events
Factor No Event Event P-value
Duration of T2DM--years (mean ± sd) Men Women
8.2 ± 6.88.0 ± 6.6
12.3 ± 7.813.0 ± 8.0
<.001<.001
Peripheral numbness-- no. (%) Men Women
170 (31%)173 (36%)
31 (52%)17 (50%)
.002
.009
Highest quartile resting pulse pressure* Men Women
109 (20%)131 (27%)
22 (37%) (17 (50%)
.003
.004
Insulin use Men Women
110 (20%)123 (25%)
20 (33%)7 (21%)
.02
.53
* > 60.3 mmHg
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Factors Associated with Cardiac EventsFactor No Event Event P-value
MEN (N=600) N=540 N=60
HbA1c % (mean ± sd) Women
7.0 ± 1.527.1 ± 1.51
7.5 ± 1.497.2 ± 1.55
.004.58
Waist-to-hip ratio (mean ± sd) Women
.94 ± .09
.89 ± .79.97 ± .08.91 ± .84
.002.28
Abnormal VR—no. (%) Women
89 (16%)89 (18%)
20 (33%)10 (34%)
.001.11
WOMEN (N=519) N=485 N=34
Family History of Heart Disease Men
98 (20%)90 (17%)
13 (38%)13 (22%)
.08
.33
Black Race Men
19 (4%)65 (12%)
1 (3%)5 (8%)
.10
.69
No Physical Activity at Baseline Men
120 (25%)129 (24%)
13 (38%)19 (32%)
.08
.18
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Factors Predicting Cardiac Events
Factor HR 95% CI P-value
Duration of T2DM (per year) Men Women
1.041.10
1.00-1.071.06-1.15
.02<.0001
HbA1c (per 1% increase) Men Women
1.201.30
1.04-1.340.99-1.68
.009.05
Highest quartile resting pulse pressure* Men Women
1.803.02
1.01-3.051.50-6.07
.046
.002
* > 60.3 mmHg
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Factors Predicting Cardiac EventsFactor HR 95% CI P-value
Men
Peripheral Numbness 2.0 1.20-3.30 .009
Waist-to-hip ratio 1.04 0.99-1.07 .05
Abnormal VR 2.03 1.20-3.50 .01
Women
Black race 0.31 0.09-1.03 .05
Insulin use 0.34 0.12-0.89 .03
Family history of heart disease 2.30 1.11-4.72 .02
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Factors Predicting Abnormal VR(Lowest quartile)
Factor OR 95% CI P-value
Black Race 0.53 0.33-0.85 .009
Insulin Use 1.45 1.02-2.10 .04
Clinical Proteinuria
3.20 1.71-6.00 .0003
Pulse Pressure 1.02 1.003-1.03 .01
Use of ACE-inhibitor
1.44 1.05-1.96 .02
Use of Beta-blocker
1.42 0.88-2.28 .15
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Conclusions
• Baseline characteristics predictive of
cardiac events in total sample
• Some differences in factors predictive of
cardiac events in men and women
• Factors associated with abnormal VR
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Limitations
• Limited by previously collected data
• Factors collected at baseline only
• Use of 2 different measurements for HR-
based tests
• Relatively small sample size when men and
women examined individually
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Strengths
• Large cohort study with 5 years of follow-up
• Comprehensive assessment of diabetes-related factors
• Extensive testing of autonomic function• Sample representative of contemporary
diabetes care
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Implications
• CAN consistently shown to be associated with adverse outcomes
• CAN preventable complication of T2DM
• Elevated BP also important contributor to cardiac risk in T2DM
• Identify high-risk individuals for both CAN and cardiac events using common clinical characteristics– Gender differences
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Thank you
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Comparisons PSA- HRV
Published Comparisons DIAD
Healthy(n=274)
CAPS(n=278)
MPIP(n=684)
Task Force All (n=1,119)
Lowest quartile
LF (ms2) 791±563 511±538 277±335 1170±416 392±534 102
HF (ms2) 229±282 201±324 129±203 975±203 191±312 38
LF:HF 4.61±965 3.60±2.43 2.75±2.13 1.5±2.0 3.3±2.9 1.3
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Comparison Automated and Holter-Obtained Readings
Mean±SD Lowest Quartile
Anscore Holter Anscore Holter
HR-DB 1.15±.11 1.13±.09 1.07 1.07
VR 1.55±.26 1.33±.23 1.37 1.17
R30:15 1.24±.14 1.22±.16 1.14 1.10
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Cardiac Autonomic Neuropathy
• Damage to autonomic nerves innervating heart and blood vessels
• Abnormalities– Resting tachycardia– Orthostatic hypotension– Exercise Intolerance
• Heart rate testing– Heart rate during deep breathing– Valsalva ratio– Heart rate after standing
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Pulse Pressure
• Resting pulse pressure: Resting
systolic and diastolic pressure taken 3x
and averaged to obtain resting pulse
pressure
• SBP-DBP=PP
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abstract• Cardiac Autonomic Neuropathy in Type 2 Diabetes: Predicting Cardiac Risk• • Aim: The role of cardiac autonomic neuropathy (CAN) has not been clearly established in the risk of cardiac disease
in patients with type 2 diabetes (T2DM). The aim of this secondary data analysis of the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study was to examine the diabetes and cardiac factors associated with CAN and its role in predicting cardiac events in older adults with T2DM. Gender differences in the CAN predictors of cardiac risk were also examined.
• • Method: In the DIAD study, older patients with T2DM (n=1119) without a baseline diagnosis of coronary artery
disease (CAD) were followed over five years. Diabetes and cardiac risk factors, as well as CAN measures were assessed at baseline; cardiac events were assessed every 6 months.
• • Results: Diabetes and cardiac factors associated with abnormal valsalva ratio (VR) included: diabetes duration
(p=.001); insulin use (p=.008); microalbumin (p<.0001); serum creatinine (p=.05); retinopathy (p=.006); erectile dysfunction (p=.03); HDL (p=.04);lipid (p=.009) and hypertension (p=.001) treatment; systolic BP (p=.004) ; and resting heart rate (p=.0007). Over 5 years of follow-up, 94 (8.4%) subjects experienced a cardiac event. CAN factors predictive of an event included: highest pulse pressure (HR=2.04; p=.001) and lowest VR (HR=1.58; p=.04). In analyzing men alone, lowest VR was even higher risk (HR=2.03; p=.01); in women only, highest pulse pressure was a higher risk (HR=3.02; p=.002).
• • Conclusions: Results highlight factors that may allow healthcare providers to identify asymptomatic patients with
T2DM who are more likely to have CAN and are at risk for symptomatic cardiac disease.
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Background and Significance
Cardiovascular Disease Deaths
Prevalence of Type 2 Diabetes (T2DM)
Role of Cardiac Autonomic Neuropathy
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T2DM
• Age ≥ 20 years: 25.6 million
(11.3%)
• Age ≥ 65 years: 10.9 million
(26.9%)
• T2DM = 90-95%
• Leading cause of:
• Kidney failure
• Non-traumatic lower limb
amputations
• New cases blindness
• Annual cost: $174 billion
• Diabetic Neuropathies
2011 Diabetes Fact Sheet (CDC)
%
CDC 2011
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Cardiovascular Disease Deaths in Diabetes
CDC 2010
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Cardiac Autonomic Neuropathy (CAN)
• Damage to autonomic nerves to heart & blood vessels
• Abnormalities – Resting tachycardia– Orthostatic hypotension– Exercise intolerance
• Associated with silent ischemia, cardiomyopathy• Predictor– All cause and cardiovascular mortality