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

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

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

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

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

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

Measures

• Baseline assessment

• Sociodemographic

• Diabetes-related

• Cardiac risk factors

• Testing for CAN

• Cardiac events collected every 6 months

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

Data Analysis

• SAS 9.2

• Spearman Correlation

• Chi-square and t-tests

• Logistic Regression

• Cox Proportional Hazards

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

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

Cardiac Events over 5 Years

• 8.4% (n=94) had cardiac events

• Cardiac death

• Acute coronary syndrome

• Heart failure

• Revascularization

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

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

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

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

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

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

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

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

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

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

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

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

Thank you

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

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

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

Pulse Pressure

• Resting pulse pressure: Resting

systolic and diastolic pressure taken 3x

and averaged to obtain resting pulse

pressure

• SBP-DBP=PP

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.

Background and Significance

Cardiovascular Disease Deaths

Prevalence of Type 2 Diabetes (T2DM)

Role of Cardiac Autonomic Neuropathy

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

Cardiovascular Disease Deaths in Diabetes

CDC 2010

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