Sudden cardiac death, also known as primary cardiac arrest (PCA), is a major cause of mortality among diabetic patients and typically occurs in the setting of coronary heart disease. Because it can occur as the first clinical manifestation of coronary heart disease, identifying diabetic patients at risk of PCA remains challenging. Interrelated sequelae of diabetes, including QT prolongation and autonomic failure (1, 2), have been repeatedly implicated in the pathophysiology of PCA (36). However, it remains unknown whether the QT interval on a 12-lead electrocardiogram (ECG) has potential utility in risk stratification of diabetic patients without prior physician-diagnosed heart disease for PCA (712).

We therefore conducted a case-control study of PCA in a large prepaid health plan, Group Health Cooperative of Puget Sound. We included patients age 18–79 years who were enrolled for ≥1 year or had four or more clinic visits in the prior year, had physician-diagnosed diabetes noted in their ambulatory care medical record or were treated with oral hypoglycemics or insulin, and had an ECG recorded before their index date (see below). We excluded enrollees with prior physician-diagnosed heart disease (Table 1).

Patients were diabetic enrollees who experienced out-of-hospital PCA (a sudden, pulseless condition without a known noncardiac cause) between 1 January 1980 and 31 December 1994. We identified potential cases from Seattle and suburban King County emergency medical service incident reports and Group Health Cooperative of Puget Sound death records. Potential control subjects were a stratified random sample of diabetic enrollees, frequency matched to all cases within groups defined by age in decades, sex, and index year. We used information from ambulatory care medical records, physician-reviewed emergency medical service incident reports, and autopsy reports (when available) to exclude patients with prior, noncardiac, life-threatening conditions (13). We defined an index date for each case as the date of PCA. We randomly assigned an index date to each control subject from the distribution of case index dates.

Abstractors recorded clinical characteristics and laboratory values of enrollees before the index date from ambulatory care medical records. The EPICARE Center estimated the QT index (QTI; %) and the T-wave negativity, ST-segment depression, and Q-wave scores (unitless) from photocopied ECGs according to Novacode criteria (14, 15). We determined treatment with medications at the index date using computerized pharmacy records. These measures have been defined and their characteristics described elsewhere (1621).

Cases (n = 79) and control subjects (n = 214) were similar in age (65.4 ± 0.6 vs. 65.7 ± 0.3 years), race (90 vs. 94% white), smoking status (22 vs. 17% current), history of type 2 diabetes (97 vs. 98%), hypertension (52 vs. 52%), systolic/diastolic blood pressure (142 ± 2 vs. 143 ± 1/80 ± 1 vs. 81 ± 1 mmHg), and BMI (27.6 ± 0.6 vs. 28.8 ± 0.4 kg/m2). However, cases had longer duration diabetes (11.6 ± 1.2 vs. 9.0 ± 0.7 years, P = 0.07), more metabolic complications (14 vs. 6%, P = 0.03), and cerebrovascular disease (33 vs. 7%, P < 0.01). Although the ECG date–index date interval was similar in cases and control subjects (5.1 ± 0.6 vs. 5.5 ± 0.5 years), cases also had a higher mean heart rate (80 ± 2 vs. 75 ± 1 bpm, P = 0.02), QTI (109 ± 1 vs. 103 ± 1%, P < 0.01), Q-wave score (6.5 ± 0.9 vs. 3.7 ± 0.6, P = 0.01), ST-segment depression score (4.0 ± 0.7 vs. 1.9 ± 0.4, P = 0.01), and T-wave negativity score (4.0 ± 0.8 vs. 2.1 ± 0.5, P = 0.04). Remaining ECG, medication, lab, and clinical measures were comparable.

In conditional logistic regression models adjusted for sampling design, age, and race, risk of PCA was increased 3.5 (1.6–7.6)-fold in the fourth versus first QTI quartile, but there was little evidence of increased risk for diabetic patients in the second and third quartiles (Table 1). Effects of further adjustment were modest (Table 1). Comparing the upper with the lower three quartiles combined produced similar findings but narrowed the 95% confidence limits around the point estimates: 3.6 (2.0–6.3) (age and race), 3.1 (1.6–6.1) (clinical), 2.7 (1.2–5.9) (ECG), and 2.7 (1.3–5.4) (autonomic). Effects of controlling for the ECG date–index date interval, substituting Bazett’s heart-rate corrected QT (QTc) for QTI (22, 23) and weighting for the probability of ECG availability (24, 25) were negligible.

This is the first population-based study to examine the risk of PCA associated with QT prolongation in predominantly type 2 diabetic patients without prior physician-diagnosed heart disease (26). Diabetic patients in the upper quartile of the QTI distribution (i.e., with a QTI >107%) had a threefold increased risk of PCA after accounting for clinical and other ECG or autonomic characteristics.

Whether the increased risk reflects direct effects of previously undiagnosed myocardial damage, autonomic failure, or both remains unknown, but we excluded enrollees with prior physician-diagnosed heart disease and were unable to attribute the association to differences in clinical characteristics or subclinical ischemia and infarction. Similarly, adjustment for symptomatic dysautonomia, use of β-blockers and tricyclic antidepressants, and measures of heart rate and RR variation only modestly attenuated the increased risk of PCA. Moreover, results were unchanged by controlling for the ECG date–index date interval, substituting QTc, or weighting for ECG availability.

These findings suggest that QT prolongation may be useful in risk stratifying populations of predominantly white, type 2 diabetic patients for PCA. Whether the findings are generalizable to diabetic patients who are nonwhite and those with prior angina, myocardial infarction, and/or congestive heart failure remains unknown. Further research is needed to determine whether clinical interventions to reduce QTI (2, 2729) decrease the risk of PCA among diabetic patients.

National Institutes of Health Grants HL-42456-03, 5-T32-HL07055, and the VAPSHCS HSRD Post-Doctoral Fellowship Program funded this study.

The preliminary findings for this study were published as an abstract (30).

1.
Whitsel EA, Boyko EJ, Siscovick DS: Reassessing the role of QTc in the diagnosis of autonomic failure among patients with diabetes.
Diabetes Care
23
:
241
–247,
2000
2.
Whitsel EA, Boyko EJ, Siscovick DS: Accuracy of QTc and QTI for detection of autonomic dysfunction.
Ann Noninvasive Electrocardiol
4
:
257
–266,
1999
3.
Kahn JK, Sisson JC, Vinik AI: QT interval prolongation and sudden cardiac death in diabetic autonomic neuropathy.
J Clin Endocrinol Metab
64
:
751
–754,
1987
4.
Bellavere F, Ferri M, Guarini L, Bax G, Piccoli A, Cardone C, Fedele D: Prolonged QT period in diabetic autonomic neuropathy: a possible role in sudden cardiac death?
Br Heart J
59
:
379
–383,
1988
5.
Ewing DJ, Boland O, Neilson JMM, Cho CG, Clarke BF: Autonomic neuropathy, QT interval lengthening, and unexpected deaths in male diabetic patients.
Diabetologia
34
:
182
–185,
1991
6.
Ong JJ, Sarma JSM, Venkataraman K, Levin SR, Singh BN: Circadian rhythmicity of heart rate and QTc interval in diabetic autonomic neuropathy: implications for the mechanism of sudden cardiac death.
Am Heart J
125
:
744
–752,
1993
7.
Rea TD, Pearce RM, Raghunathan TE, Lemaitre RN, Sotoodehnia N, Jouven X, Siscovick DS: Incidence of out-of-hospital cardiac arrest.
Am J Cardiol
93
:
1455
–1460,
2004
8.
Albert CM, Chae CU, Grodstein F, Rose LM, Rexrode KM, Ruskin JN, Stampfer MJ, Manson JE: Prospective study of sudden cardiac death among women in the United States.
Circulation
107
:
2096
–2101,
2003
9.
Jouven X, Desnos M, Guerot C, Ducimetière P: Predicting sudden death in the population: the Paris Prospective Study I.
Circulation
99
:
1978
–1983,
1999
10.
de Vreede-Swagemakers JJ, Gorgels AP, Weijenberg MP, Dubois-Arbouw WI, Golombeck B, van Ree JW, Knottnerus A, Wellens HJ: Risk indicators for out-of-hospital cardiac arrest in patients with coronary artery disease.
J Clin Epidemiol
52
:
601
–607,
1999
11.
Kannel WB, Wilson PW, D’Agostino RB, Cobb J: Sudden coronary death in women.
Am Heart J
136
:
205
–212,
1998
12.
Escobedo LG, Caspersen CJ: Risk factors for sudden coronary death in the United States.
Epidemiology
8
:
175
–180,
1997
13.
Siscovick DS: Challenges in cardiac arrest research: data collection to assess outcomes.
Ann Emerg Med
22
:
92
–98,
1993
14.
Epidemiological Cardiology Research (EPICARE) Center, Wake Forest University School of Medicine, Department of Public Health Sciences, Winston-Salem, NC. Available from www.phs.wfubmc.edu/center_epicare.cfm. Accessed 15 January
2005
15.
Rautaharju PM, Park LP, Chaitman BR, Rautaharju F, Zhang Z: The Novacode criteria for classification of ECG abnormalities and their clinically significant progression and regression.
J Electrocardiol
31
:
157
–187,
1998
16.
Rautaharju PM, Warren JW, Calhoun HP: Estimation of QT prolongation: a persistent, avoidable error in computer electrocardiography.
J Electrocardiol
23 (Suppl.):111–117, 1991
17.
Rautaharju PM, Zhang ZM: Linearly scaled, rate-invariant normal limits for QT interval: eight decades of incorrect application of power functions.
J Cardiovasc Electrophysiol
13
:
1211
–1218,
2002
18.
Zhou SH, Wong S, Rautaharju PM, Karnik N, Calhoun HP: Should the JT rather than the QT interval be used to detect prolongation of ventricular repolarization? An assessment in normal conduction and in ventricular conduction defects.
J Electrocardiol
25 (Suppl.)
:
131
–136,
1992
19.
Rautaharju PM, Zhang ZM, Prineas R, Heiss G: Assessment of prolonged QT and JT intervals in ventricular conduction defects.
Am J Cardiol
93
:
1017
–1021,
2004
20.
Rautaharju PM, Park LP, Gottdiener JS, Siscovick D, Boineau R, Smith V, Powe NR: Race- and sex-specific ECG models for left ventricular mass in older populations: factors influencing overestimation of left ventricular hypertrophy prevalence by ECG criteria in African-Americans.
J Electrocardiol
33
:
205
–218,
2000
21.
Whitsel EA, Raghunathan TE, Pearce RM, Lin D, Rautaharju PM, Lemaitre R, Siscovick DS: RR interval variation, the QT interval index and risk of primary cardiac arrest among patients without clinically recognized heart disease.
Eur Heart J
22
:
165
–173,
2001
22.
Bazett HC: An analysis of the time-relations of electrocardiograms.
Heart
7
:
353
–370,
1920
23.
Moss AJ, Zareba W, Benhorin J, Couderc JP, Kennedy H, Locati-Heilbron E, Maison-Blanche P: ISHNE guidelines for electrocardiographic evaluation of drug-related QT prolongation and other alterations in ventricular repolarization: task force summary.
Ann Noninvasive Electrocardiol
6
:
333
–341,
2001
24.
Raghunathan TE, Solenberger PW, Van Hoewyk J: IVEware: imputation and variance estimation software. Survey Methodology Program, Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI. Available from www.isr.umich.edu/src/smp/ive. Accessed 21 November
2005
25.
Raghunathan TE: What do we do with missing data? Some options for analysis of incomplete data.
Ann Rev Public Health
25
:
99
–117,
2004
26.
Whitsel EA: Studies of the association between measures of QT prolongation, risk of coronary heart disease and primary cardiac arrest. Available from www.unc.edu/∼ewhitsel/qt-chd-pca.html. Accessed 7 June
2005
27.
Ahnve S, Erhardt L, Lundman T, Rehnqvist N, Sjögren A: Effect of metoprolol on QTc intervals after acute myocardial infarction.
Acta Med Scand
208
:
223
–228,
1980
28.
Nyberg G, Vedin A, Wilhelmsson C: QT time in patients treated with alprenolol or placebo after myocardial infarction.
Br Heart J
41
:
452
–455,
1979
29.
Moss AJ, Zareba W, Hall WJ, Schwartz PJ, Crampton RS, Benhorin J, Vincent GM, Locati EH, Priori SG, Napolitano C, Medina A, Zhang L, Robinson JL, Timothy K, Towbin JA, Andrews ML: Effectiveness and limitations of β-blocker therapy in congenital long-QT syndrome.
Circulation
101
:
616
–623,
2000
30.
Whitsel EA, Boyko EJ, Rautaharju PM, Raghunathan TE, Pearce RM, Siscovick DS: QT interval prolongation and risk of primary cardiac arrest in diabetic patients without clinically recognized heart disease (Abstract).
Circulation
101
:
716
,
2000

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