View metadata, citation and similar papers at core.ac.uk brought to you by CORE Journal of the American College of Cardiology providedVol. by Elsevier 43, No. - 4,Publisher 2004 Connector © 2004 by the American College of Cardiology Foundation ISSN 0735-1097/04/$30.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2003.09.040 Risk Predictors and Coronary Disease Heart Rate-Corrected QT Interval Prolongation Predicts Risk of Coronary Heart Disease in Black and White Middle-Aged Men and Women The ARIC Study Jacqueline M. Dekker, PHD,*† Richard S. Crow, MD,‡ Peter J. Hannan, MSTAT,‡ Evert G. Schouten, MD, PHD,* Aaron R. Folsom, MD, MPH‡ Wageningen and Amsterdam, the Netherlands; and Minneapolis, Minnesota OBJECTIVES We aimed to study the predictive value of heart rate-corrected QT interval (QTc) for incident coronary heart disease (CHD) and cardiovascular disease (CVD) mortality in the black and white general population, and to validate various QT measurements. BACKGROUND QTc prolongation is associated with higher risk of mortality in cardiac patients and in the general population. Little is known about the association with incident CHD. No previous studies included black populations. METHODS We studied the predictive value of QTc prolongation in a prospective population study of 14,548 black and white men and women, age 45 to 64 year. QT was determined by the NOVACODE program in the digital electrocardiogram recorded at baseline. RESULTS In quintiles of QTc, cardiovascular risk profile deteriorated with longer QTc, and risk of CHD and CVD mortality increased. The high risk in the upper quintile was mostly explained by the 10% with the longest QTc. The age-, gender-, and race-adjusted hazard ratios for CVD mortality and CHD in subjects with the longest 10% relative to the other 90% of the gender-specific QTc distribution were 5.13 (95% confidence interval 3.80 to 6.94) and 2.14 (95% confidence interval 1.71 to 2.69), respectively. The increased risk was partly, but not completely, attributable to other risk factors or the presence of chronic disease. The association was stronger in black than in white subjects. Manual- and machine-coded QT intervals were highly correlated, and the method of rate correction did not affect the observed associations. CONCLUSIONS Long QTc is associated with increased risk of CHD and CVD mortality in black and white healthy men and women. (J Am Coll Cardiol 2004;43:565–71) © 2004 by the American College of Cardiology Foundation The heart rate-corrected QT (QTc) interval in the resting QT interval have been reported (11), there is no information 12-lead electrocardiogram (ECG) provides important prog- about the association of QTc with CVD mortality or incident nostic information in clinical practice. In post-myocardial CHD in the black population. Therefore, we studied QT in infarction patients (1), subjects referred for Holter monitor- relation to risk of CHD incidence and CVD mortality in a ing (2), and subjects with diabetes (3) QTc prolongation is large biracial U.S. population study, the Atherosclerosis Risk In Communities (ARIC) study. See page 572 Because measurement of QT is hampered by systematic differences between manual coders and between computerized associated with mortality risk. In inheritable syndromes, which QT measurements of different ECG systems (12), manually are characterized by QTc prolongation, affected patients have determined QT intervals were compared with machine- high risk of sudden death (4). Also, in several population derived QT intervals. In addition, to compare QT intervals studies (5–10), increased risk of cardiovascular disease (CVD) between subjects, adjustment for differences in heart rate is mortality was observed in subjects with QTc prolongation. essential. The widely used Bazett formula is known to over- Less is known about the association with incident coronary adjust at very high and low heart rates, and several alternative heart disease (CHD). Furthermore, though racial differences in methods have been proposed (13,14). We compared three commonly used formulae for the correction of heart rate. From the *Department of Epidemiology and Public Health, Wageningen Univer- sity, Wageningen, The Netherlands, †Institute for Research in Extramural Medicine, METHODS VU University Medical Center, Amsterdam, The Netherlands; and the ‡Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, Study population. The ARIC study is following a cohort Minnesota. Supported by a grant from the Netherlands Organization for Scientific of 15,792 middle-aged men and women (15). During 1987 Research (NWO) (Dr. Dekker). Manuscript received December 13, 2002; revised manuscript received August 15, to 1989, population samples were drawn from the 45- to 2003, accepted September 17, 2003. 64-year-old inhabitants of Forsyth County, North Carolina; 566 Dekker et al. JACC Vol. 43, No. 4, 2004 QT and CHD Risk in the General Population February 18, 2004:565–71 dardized B-mode ultrasonic technique (20). Use of cardiac Abbreviations and Acronyms medication was defined as self-reported use of medication ARIC ϭ Atherosclerosis Risk In Communities study for angina pectoris, heart failure, or rhythm disturbances CHD ϭ coronary heart disease during the last two weeks. ϭ CVD cardiovascular disease Methods of follow-up. The method of follow-up has been ECG ϭ electrocardiogram QTc ϭ heart rate-corrected QT interval described previously (21). Briefly, interviewers contacted participants annually by telephone to identify hospitaliza- tions and deaths. Death certificates and discharge lists from Jackson, Mississippi; the northwest suburbs of Minneapolis, local hospitals were surveyed by ARIC staff to detect Minnesota; and Washington County, Maryland; they were additional deaths and cardiovascular events. For hospital- invited for a home interview and a clinical examination. In ized patients with potential acute CHD events, trained Jackson, 46% of eligible subjects participated; approximately abstractors recorded the presenting signs and symptoms, 65% participated in the other three centers. For the present including chest pain, cardiac enzymes, and related clinical study, subjects with a self-reported history of physician- information. Up to three 12-lead ECGs were visually coded diagnosed heart attack, prior cardiovascular surgery or using the Minnesota Code, and wave-form evolution was coronary angioplasty, or with 12-lead Minnesota Code evaluated using side-by-side comparisons. Out-of-hospital evidence of prior myocardial infarction were excluded, deaths were investigated by means of the death certificate leaving 14,672 subjects. After exclusion of subjects with and, in most cases, an interview with next of kin and missing data on QT, the study population consists of 14,548 questionnaires completed by the patients’ physicians. Cor- men and women. oner reports and autopsy reports, when available, were used Baseline measurements. In the home interview, questions in validation. All potential in- and out-of-hospital clinical were asked about health behaviors, sociodemographics, and CHD events were reviewed and adjudicated by the ARIC disease history. The clinical examination included electro- Morbidity and Mortality Classification Committee using cardiography. After resting 5 to 10 min while electrodes published criteria (21). were placed, a standard 12-lead ECG and a 2-min paper In the present study, follow-up data through 1993 were recording of a three-lead (leads V , II, and V ) rhythm strip 1 5 used. Follow-up information on incident CHD and mor- were made in the supine position. The QT interval from the tality was complete for 95%. The CHD incidence was digital 12-lead ECG was determined by the NOVACODE defined as definite or probable myocardial infarction, cardiac program (16). The NOVACODE program generates an revascularization procedures (excluding thrombolytic ther- average waveform derived from all 12 simultaneously mea- apy), or definite CHD death. Cardiovascular disease mor- sured leads. This allows the system to determine the QT tality was based on the underlying cause from the death from the earliest QRS onset to the latest offset of the certificates: ICD-9 codes 390 to 459. T-wave. All NOVACODE measurements were visually verified. When measurements between computer and oper- Manual QT measurement. QT was manually determined ator differed by Ͼ5 ms, the operator’s reference points were in a case-cohort sample from the ARIC study (21), consist- used. Plasma total cholesterol and triglycerides were mea- ing of a random sample of 900 subjects, all incident CHD sured by enzymatic methods (17,18), and low-density li- cases, and all deaths. Measurements were performed at the poprotein cholesterol was calculated using the Friedewald University of Minnesota ECG Coding Center, using a formula. High-density lipoprotein cholesterol was measured digitizing tablet (Calcomp, Columbia, Maryland) and a after dextran-magnesium precipitation of non–high-density personal computer. Coders mounted the 3-lead two-min lipoproteins (19). Serum insulin was measured using a rhythm strip on the tablet, and used the mouse to mark QT radioimmunoassay (125I Insulin Kit, Cambridge Medical onset and T-wave offset and preceding RR intervals in three Diagnostics, Billerica, Massachusetts). Serum glucose was consecutive normal beats in all three leads. T-wave offset assessed by the hexokinase method. Prevalent diabetes was defined as the point of maximum change of slope as the mellitus was defined as a fasting glucose level of 126 mg/dl T-wave merges with the baseline (6). This accords with the (7.0 mmol/l) or more, nonfasting glucose level of 200 mg/dl method applied in the NOVACODE program (16). The (11.1 mmol/l) or more, and/or a history of, or treatment for, inter- and intracoder variability was evaluated by means of diabetes. Three seated blood pressure measurements were analysis of variance in a set of 10 ECGs, which were taken on the right arm, using a random-zero sphygmoma- measured three times by each coder. The QT interval was nometer. The mean of the last two measurements was used. used as the dependent variable.