- Email: [email protected]
Association between heart rate–corrected QT interval and coronary risk factors in 2,894 healthy subjects (the DESIR study)
Association Between Heart Rate–Corrected QT Interval and Coronary Risk Factors in 2,894 Healthy Subjects (The DESIR Study) Laurent Fauchier, MD, Pierre Maison-Blanche, MD, Anne Forhan, MSc, Alain D’Hour, MD, Patrick Le´pinay, MD, Jean Tichet, MD, Sylviane Vol, MSc, Philippe Coumel, MD, Jean Paul Fauchier, MD, Beverley Balkau, PhD, and the DESIR Study Group* he prolongation of the Bazett-corrected QT interval (QTc ⫽ QT/RR , where RR ⫽ 60/heart rate) T is associated with an increased risk of ventricular 1/2
arrhythmias, sudden death, and/or coronary artery disease in patients with the long QT syndrome or diabetic neuropathy and after myocardial infarction.1– 4 A prolonged heart rate– corrected QT interval is also an independent risk factor for cardiac mortality in patients without cardiac dysfunction, and it may therefore help for cardiovascular risk stratification in the general population.5– 8 However, the association between a prolonged QTc and sudden death has not been found in the Framingham Study.9 There is little information concerning the QT duration and its relation to coronary risk factors in apparently healthy subjects.10 The aim of this study was to evaluate these relations. •••
The study population consisted of men and women, aged 30 to 64 years at inclusion in the Data from an Epidemiological Study on the Insulin Resistance syndrome (DESIR) study.11 Participants were recruited from volunteers insured by the French social security system, which offers periodic health examinations free of charge and were issued from 10 health examination centers in the western central part of France. All subjects signed an informed consent form. Between 1994 and 1996, 4,148 of the 5,214 subjects participating in this study had a 12-lead electrocardiogram (Cardionics, 25 mm/s, Brussels, Belgium) recorded. A healthy population of 2,894 subjects (1,395 From the Service de Cardiologie B et Laboratoire d’e´lectrophysiologie cardiaque, Centre Hospitalier Universitaire Trousseau, Tours; INSERM Unit 258 and Faculte´ de Me´decine Paris-Sud, Villejuif; Service de Cardiologie, Hoˆpital Lariboisie`re, Paris; Centre d’Examens de Sante´, Le Mans and Orle´ans; and IRSA, La Riche, France. The DESIR project was supported by cooperative contracts between the Institut National de la Sante´ et de la Recherche Me´dicale (INSERM) and la Caisse Nationale de l’Assurance Maladies des Travailleurs Salarie´s (CNAMTS) (contract 3 AM004) and Novartis Pharma (convention 98297), by INSERM Re´seaux en Sante´ Publique (494003 and 4R001C) and by INSERM Interactions entre les determinants de la sante´ (4D002D), by the Association Diabe`te Risque Vasculaire, the Fe´de´ration Franc¸aise de Cardiologie, and La Fondation de France. Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Lipha Pharmaceuticals, Novo Nordisk, Pierre Fabre, and Topcon have also contributed to the funding of this study. Dr. Fauchier’s address is: Service de Cardiologie B., Centre Hospitalier Universitaire Trousseau, 37044 Tours Cedex, France. E-mail:[email protected]. Manuscript received January 11, 2000; revised manuscript received and accepted March 13, 2000. *See Appendix for members of the DESIR Study Group. ©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 86 September 1, 2000
men and 1,499 women) were selected after exclusion for the following criteria: absence of sinus rhythm on electrocardiogram, intraventricular conduction defect on electrocardiogram, coronary artery disease (information obtained by medical questionnaire or by electrocardiogram analysis), or use of anti-ischemic agents, use of medication that might affect QT interval duration (antiarrhythmic agents, neuroleptic drugs, diuretics, antihistaminic drugs), diabetes (information obtained by medical questionnaire or use of antidiabetic drugs or fasting glucose ⱖ1.26 g/L), hypertension (systolic blood pressure ⱖ160 mm Hg and/or diastolic blood pressure ⱖ95 mm Hg), or use of antihypertensive treatment. Smoking habits and alcohol consumption were assessed by means of a selfadministered questionnaire. The physical activity score was based on 3 questions in a self-questionnaire about physical activity at work, sporting activity, and physical activity at home, with a possibility of 4 qualitative responses to each. Subjects were classified as having an “intense” physical activity if they indicated an intense activity for any 1 of these 3 questions. All subjects had a determination of fasting glucose, glycated hemoglobin (HbA1c), insulin, total cholesterol, triglycerides, high-density and low-density lipoprotein cholesterol, lipoprotein(a) and fibrinogen concentrations, blood pressures after 5 minutes of rest, body mass index (kg/m2), and the waist-hip ratio. Electrocardiographic recordings were performed at rest and validated by a cardiologist. On each derivation, the Cardionics algorithm measured QT interval from the first deflection of the QRS complex to the return of the T wave to the isoelectric line. In case of a U wave, the end of the T wave was defined as the lower point of the curve between T and U waves. On each derivation, the mean of the QT and RR intervals was calculated from all available sinus beats (except the first and the 2 last). The QT interval duration was defined as the mean of the 12 individual values. The rate correction index k was determined from the bestfit regression between variables QT and RR: QTk ⫽ QT/RRk (k estimated at 0.354 for men, 0.338 for women). The association between various cardiovascular risk factors and the QTk duration was assessed by Spearman correlation coefficients, adjusted for age and other cardiovascular risk factors. The QTk interval was not related to heart rate (percentage of variation was equal to 0%, p ⬎0.3); because this rate correction index was close to 1⁄3, the 0002-9149/00/$–see front matter PII S0002-9149(00)01015-8
557
TABLE I Spearman Correlation Coefficients Adjusted on Age (p value), with Heart Rate and Heart Rate–Corrected QT Interval (QTk) in a Healthy Population of 1,395 Men and 1,499 Women from the DESIR Study Heart Rate Variables Body mass index Waist-hip ratio Systolic blood pressure Diastolic blood pressure Glucose HbA1c Insulin Cholesterol Triglycerides HDL cholesterol LDL cholesterol* Lipoprotein (a) Fibrinogen
QTk Interval
Men 0.06 (0.02) 0.17 (0.0001) 0.15 (0.0001) 0.15 (0.0001) 0.11 (0.0001) 0.12 (0.0001) 0.19 (0.0001) 0.1.1 (0.0001) 0.11 (0.0001) ⫺0.02 (0.4) 0.09 (0.0008) ⫺0.02 (0.5) 0.11 (0.0001)
Women 0.09 0.13 0.15 0.14 0.21 0.10 0.19 0.04 0.12 ⫺0.03 0.02 ⫺0.01 0.10
(0.0003) (0.0001) (0.0001) (0.0001) (0.0001) (0.0001) (0.0001) (0.09) (0.0001) (0.3) (0.6) (0.7) (0.0002)
Men ⫺0.01 (0.7) ⫺0.11 (0.0001) ⫺0.04 (0.2) ⫺0.05 (0.05) ⫺0.02 (0.4) ⫺0.09 (0.0006) ⫺0.09 (0.0007) 0.02 (0.4) ⫺0.07 (0.02) 0.06 (0.03) 0.002 (0.9) 0.04 (0.1) 0.004 (0.9)
Women ⫺0.01 (0.7) ⫺0.05 (0.07) 0.01 (0.7) ⫺0.01 (0.8) ⫺0.09 (0.0007) ⫺0.11 (0.0001) ⫺0.03 (0.3) ⫺0.03 (0.3) ⫺0.02 (0.5) ⫺0.003 (0.9) ⫺0.02 (0.4) ⫺0.06 (0.3) ⫺0.06 (0.03)
*Estimated by the Dahlen formula: total cholesterol HDL cholesterol ⫺ triglycerides/5 ⫺ (lipoprotein(a)/0.3). All variables are expressed in g/L. HDL ⫽ high-density lipoprotein; LDL ⫽ low-density lipoprotein.
result was similar for Fridericia’s formula (QTf ⫽ QT/RR1/3) (0%, p ⬎0.3). In contrast, the interval calculated by Bazett’s formula was correlated with heart rate (23%, p ⬍0.001). The men had on average a heart rate– corrected interval QTk of 376 ⫾ 18 ms. There was an inverse correlation between QTk and HbA1c (r ⫽ ⫺0.09, p ⬍0.001) and fasting insulin (r ⫽ ⫺0.09, p ⬍0.001) after adjusting for age (Table I) that remained significant only for HbA1c after adjustment on age, body mass index, systolic blood pressure, total cholesterol, and triglycerides. Heart rate was significantly correlated with most of the risk factors studied. In women (QTk ⫽ 382 ⫾ 17 ms), there was an inverse correlation between QTk and HbA1c (r ⫽ ⫺0.11, p ⬍0.001) and fasting plasma glucose (r ⫽ ⫺0.09, p ⬍0.001), and these results remained significant after adjustment of other parameters. Alcohol consumption did not affect the QTk duration in men or women. In men who smoked, the number of cigarettes smoked per day was positively correlated with the QTk duration (r ⫽ 0.14, p ⫽ 0.01 after adjustment on age). High physical activity was associated with an increase in QTk in men (381 ⫾ 7 vs 376 ⫾ 17 ms in men with moderate activity and 374 ⫾ 17 ms in men with low activity; overall p ⬍0.001). •••
Besides the large number of subjects, this study about the relations between QT duration and coronary artery disease risk factors had (1) an automatic measurement of the QT interval duration (with a high reproducibility and no inter- and intraobserver variability), and (2) used a specific heart rate– correction formula for the QT interval duration. One limitation of QT measurement in screening for risk stratification is the differences between observers in manually determining the end of the T wave.8,12–14 Recent findings have suggested that computer-determined QT intervals have a high reproducibility and may differentiate patients with hypertrophic cardiomyopathy from normal subjects, or may help predict cardiac mortality in 558 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 86
the elderly.6,15,16 Because of its relation to other risk factors and its independent prognostic value, heart rate is a confounder that may have an important role in predicting mortality by the QT interval. Thus, it was important to have an adequate correction formula for the present study to evaluate more precisely the relations between corrected QT duration and coronary artery disease risk factors. Previous studies have found that the heart rate– corrected QT interval has a prognostic value, independent of other cardiovascular risk indicators such as cigarette smoking, hypertension, lipid profile, body mass index, and diabetes mellitus.6 However, one of our major findings is that the heart rate– corrected QT duration may be in part directly influenced by some coronary risk factors (glucose homeostasis, physical activity, tobacco use). The glucose homeostasis parameters were inversely related to the QTk duration. These results, different from previous studies, could be related to the use of a different rate-correction formula. The increase in sympathetic activity and ventricular inotropism by insulin may explain our results. The effect of disturbed glucose metabolism on myocardial cells with changes in cation (sodium and potassium) transport and concentrations that may modify repolarization may be another explanation. Because of the relative shortening of the corrected QT interval with an increase in glucose, insulin, and HbA1c, the mechanism of an increased risk associated with an elevation of these latter parameters could be an association with a short refractory period along with a short excitation wavelength. This would predispose to reentry rather than an increased dispersion of repolarization or early afterdepolarization. These mechanisms were suggested to explain the increased risk of the lengthening of the QT interval with increasing cardiovascular risk factors.17 The increase in QTk duration with high physical activity may be explained by a possible higher left ventricular mass. To our knowledge, the positive relation between heart rate– corrected QT duration and tobacco use has not been SEPTEMBER 1, 2000
previously reported and could be related to ischemic myocardial damage or subclinical atherosclerosis, an explanation usually suggested for the longer corrected QT associated with other risk factors.18 Thus, after correcting for heart rate, the QT duration was influenced by glucose homeostasis, tobacco consumption (with a dose-effect relation in men), and physical activity in men. These findings may help to understand the mechanisms of sudden death in apparently healthy subjects. Acknowledgment: The hypotheses were formulated by Mat Labrunie, for a short thesis.
APPENDIX The DESIR Study Group: INSERM U258: B. Balkau, P. Ducimetie`re, E. Eschwe`ge; INSERM U367: F. Alhenc-Gelas; CHU d’Angers: A. Bechetoille, Y. Gallois, A. Girault; Hoˆpital Bichat: M. Marre; Association de Cardiologie du Centre, Val de Loire: M. Brochier; Centres d’Examens de Sante´ du Re´seau 9: Alenc¸on—M.C. Chesnier; Angers—F. Rabouin; Blois—J.M. Le Mauff, J.P. Sigalas; Caen—A. Caradec, C. Geslain; Chartres—D. Arondel; Chateauroux—M. Novak; Cholet—A. Petrella; Le Mans—A. D’Hour; Orle´ans—P. Le´pinay, E. Wilpart; Tours—B. Royer; Coordinateur Administratif du Re´seau 9: N. Verstraete; Institut de Recherche en Me´decine Ge´ne´rale: Basse-Normandie—Ph. Aubourg; Center—J. Cogneau, C. Rougeron; Pays de Loire—V. Diquero; Me´de´cins Ge´neralistes des De´partements; Institut Re´gional pour la Sante´: E. Cace`s, M. Cailleau, J.M. Jacquelin, J.G. Moreau, F. Rakotozafy, J. Tichet, S. Vol.
1. Moss AJ, Schwartz PJ, Crampton RS, Tzironi D, Locati EH, MacCluer J, Hall
WJ, Weitkamp L, Vincent GM, Garson A Jr., et al. The long QT syndrome. prospective longitudinal study of 328 families. Circulation 1991;84:1136 –1144. 2. Ahnve S. QT interval prolongation in acute myocardial infarction. Eur Heart J 1985;6(suppl D):85–95. 3. Schwartz PJ, Wolf S. QT interval prolongation as predictor of sudden death in patients with myocardial infarction. Circulation 1978;57:1074 –1077. 4. Bellavere F, Ferri M, Guarini L, Bax G, Piccoli A, Cardene C, Fedele D. Prolonged QT period in diabetic autonomic neuropathy: a possible role in sudden cardiac death? Br Heart J 1988;59:379 – 83.
5. Schouten EG, Dekker JM, Meppelink P, Kok EJ, Vandenbroucke JP, Pool J. QT-interval prolongation predicts cardiovascular mortality in an apparently healthy population. Circulation 1991;84:1516 –1523. 6. de Bruyne MC, Hoes AW, Kors JA, Hofman A, van Bemmel JH, Grobbee DE. Prolonged QT interval predicts cardiac and all-cause mortality in the elderly. The Rotterdam Study. Eur Heart J 1999;20:278 –284. 7. Dekker JM. The value of the heart-rate corrected QT-interval for cardiovascular risk stratification. Eur Heart J 1999;20:250 –251. 8. Dekker JM, Schouten EG, Klootwijk P, Pool J, Kromhout D. Association between QT interval and coronary heart disease in middle-aged and elderly men. The Zutphen Study. Circulation 1994;90:779 –785. 9. Goldberg RJ, Bengtson J, Chen ZY, Anderson KM, Locati E, Levy D. Duration of the QT interval and total and cardiovascular mortality in healthy persons (The Framingham Heart Study experience). Am J Cardiol 1991;67:55–58. 10. Dekker JM, Feskens EJ, Schouten EG, Klootwijk P, Pool J, Kromhout D. QTc duration is associated with levels of insulin and glucose intolerance. The Zutphen Elderly Study. Diabetes 1996;45:376 –380. 11. Mennen LI, Balkau B, Vol S, Caces E, Eschwege E. Fibrinogen: a possible link between alcohol consumption and cardiovascular disease? DESIR Study Group. Arterioscler Thromb Vasc Biol 1999;19:887– 892. 12. Willems JL, Abreu-Lima LC, Arnaud P, van Bemmell JM, Brohet C, Degani R, Denis B, Gehring J, Graham I, van Herpen G, et al. The diagnostic performance of computer programs for the interpretation of electrocardiograms. N Engl J Med 1991;325:1767–1773. 13. Willems JL, Arnaud P, van Bemmel JH, Bourdillon PJ, Brohet C, Dalla Volta S, Andersen JD, Pegani R, Denis B, Demeester M, et al. Assessment of the performance of electrocardiographic computer programs with the use of a reference data base. Circulation 1985;71:523–534. 14. de Bruyne MC, Hoes AW, Kors JA, Dekker JM, Hofman A, van Bemmel JH, Grobbee DE. Prolonged QT interval: a tricky diagnosis? Am J Cardiol 1997;80: 1300 –1304. 15. Savelieva I, Yi G, Guo X, Hnatkova K, Malik M. Agreement and reproducibility of automatic versus manual measurement of QT interval and QT dispersion. Am J Cardiol 1998;81:471– 477. 16. Savelieva I, Yap YG, Yi G, Guo X, Camm AJ, Malik M. Comparative reproducibility of QT, QT peak, and T peak-T end intervals and dispersion in normal subjects, patients with myocardial infarction, and patients with hypertrophic cardiomyopathy. Pacing Clin Electrophysiol 1998;21(11 Pt 2):2376 –2381. 17. Zipes DP. The Long QT Interval Syndrome. A Rosetta stone for sympathetic related ventricular tachyarrhythmias. Circulation 1991;84:1414 –1419. 18. Festa A, D’Agostino R Jr, Rautaharju P, O’Leary DH, Rewers M, Mykkanen L, Haffner SM. Is QT interval a marker of subclinical atherosclerosis in nondiabetic subjects? The Insulin Resistance Atherosclerosis Study (IRAS). Stroke 1999;30:1566 –1571.
Continuous Intravenous Diltiazem Infusion for Short-Term Ventricular Rate Control in Children Robert H. Pass,
MD,
Leonardo Liberman, MD, Majid Al-Fayaddh, and Allan J. Hordof, MD
iltiazem is a calcium channel antagonist that has been demonstrated to be effective in controlling the D ventricular rate in settings of atrial flutter and fibrillation in adults.1– 6 Use of this agent for this indication in children has not previously been described. Despite potentially favorable effects of calcium antagonists on the atrioventricular node, many of the available agents can have direct negative effects on ventricular function, and at least 1 is relatively contraindicated in young infants.7–9 From the Pediatric Arrhythmia Service-Division of Pediatric Cardiology, Babies and Children’s Hospital of New York, New York Presbyterian Medical Center, Columbia Campus, New York; and Division of Pediatric Cardiology, New York Presbyterian Medical Center-Cornell Campus, New York, New York. Dr. Pass’ address is: Babies and Children’s Hospital of New York, 3959 Broadway 2 North, New York, New York 10032-3784. E-mail: [email protected]. Manuscript received December 3, 1999; revised manuscript received and accepted March 13, 2000. ©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 86 September 1, 2000
MD,
Patrick Flynn,
MD,
We describe the use of diltiazem in a group of children with atrial arrhythmias for whom definitive therapy for their primary arrhythmia was necessarily, temporarily delayed. As the numbers of survivors of surgery for complex congenital heart disease increase, the numbers of patients with primary atrial arrhythmias will also increase, making appropriate acute management of this patient population increasingly important. •••
The records of all patients who received intravenous diltiazem for ventricular rate control from September 1995 to May 1999 at New York Presbyterian Hospital (Columbia and Cornell campuses) were reviewed with particular emphasis on drug efficacy and adverse effects. During that time period, 10 patients were treated with intravenous diltiazem. Table I reviews the ages, diagnoses (arrhythmic), and other salient information about patients included in this 0002-9149/00/$–see front matter PII S0002-9149(00)01016-X
559
arrhythmias, sudden death, and/or coronary artery disease in patients with the long QT syndrome or diabetic neuropathy and after myocardial infarction.1– 4 A prolonged heart rate– corrected QT interval is also an independent risk factor for cardiac mortality in patients without cardiac dysfunction, and it may therefore help for cardiovascular risk stratification in the general population.5– 8 However, the association between a prolonged QTc and sudden death has not been found in the Framingham Study.9 There is little information concerning the QT duration and its relation to coronary risk factors in apparently healthy subjects.10 The aim of this study was to evaluate these relations. •••
The study population consisted of men and women, aged 30 to 64 years at inclusion in the Data from an Epidemiological Study on the Insulin Resistance syndrome (DESIR) study.11 Participants were recruited from volunteers insured by the French social security system, which offers periodic health examinations free of charge and were issued from 10 health examination centers in the western central part of France. All subjects signed an informed consent form. Between 1994 and 1996, 4,148 of the 5,214 subjects participating in this study had a 12-lead electrocardiogram (Cardionics, 25 mm/s, Brussels, Belgium) recorded. A healthy population of 2,894 subjects (1,395 From the Service de Cardiologie B et Laboratoire d’e´lectrophysiologie cardiaque, Centre Hospitalier Universitaire Trousseau, Tours; INSERM Unit 258 and Faculte´ de Me´decine Paris-Sud, Villejuif; Service de Cardiologie, Hoˆpital Lariboisie`re, Paris; Centre d’Examens de Sante´, Le Mans and Orle´ans; and IRSA, La Riche, France. The DESIR project was supported by cooperative contracts between the Institut National de la Sante´ et de la Recherche Me´dicale (INSERM) and la Caisse Nationale de l’Assurance Maladies des Travailleurs Salarie´s (CNAMTS) (contract 3 AM004) and Novartis Pharma (convention 98297), by INSERM Re´seaux en Sante´ Publique (494003 and 4R001C) and by INSERM Interactions entre les determinants de la sante´ (4D002D), by the Association Diabe`te Risque Vasculaire, the Fe´de´ration Franc¸aise de Cardiologie, and La Fondation de France. Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Lipha Pharmaceuticals, Novo Nordisk, Pierre Fabre, and Topcon have also contributed to the funding of this study. Dr. Fauchier’s address is: Service de Cardiologie B., Centre Hospitalier Universitaire Trousseau, 37044 Tours Cedex, France. E-mail:[email protected]. Manuscript received January 11, 2000; revised manuscript received and accepted March 13, 2000. *See Appendix for members of the DESIR Study Group. ©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 86 September 1, 2000
men and 1,499 women) were selected after exclusion for the following criteria: absence of sinus rhythm on electrocardiogram, intraventricular conduction defect on electrocardiogram, coronary artery disease (information obtained by medical questionnaire or by electrocardiogram analysis), or use of anti-ischemic agents, use of medication that might affect QT interval duration (antiarrhythmic agents, neuroleptic drugs, diuretics, antihistaminic drugs), diabetes (information obtained by medical questionnaire or use of antidiabetic drugs or fasting glucose ⱖ1.26 g/L), hypertension (systolic blood pressure ⱖ160 mm Hg and/or diastolic blood pressure ⱖ95 mm Hg), or use of antihypertensive treatment. Smoking habits and alcohol consumption were assessed by means of a selfadministered questionnaire. The physical activity score was based on 3 questions in a self-questionnaire about physical activity at work, sporting activity, and physical activity at home, with a possibility of 4 qualitative responses to each. Subjects were classified as having an “intense” physical activity if they indicated an intense activity for any 1 of these 3 questions. All subjects had a determination of fasting glucose, glycated hemoglobin (HbA1c), insulin, total cholesterol, triglycerides, high-density and low-density lipoprotein cholesterol, lipoprotein(a) and fibrinogen concentrations, blood pressures after 5 minutes of rest, body mass index (kg/m2), and the waist-hip ratio. Electrocardiographic recordings were performed at rest and validated by a cardiologist. On each derivation, the Cardionics algorithm measured QT interval from the first deflection of the QRS complex to the return of the T wave to the isoelectric line. In case of a U wave, the end of the T wave was defined as the lower point of the curve between T and U waves. On each derivation, the mean of the QT and RR intervals was calculated from all available sinus beats (except the first and the 2 last). The QT interval duration was defined as the mean of the 12 individual values. The rate correction index k was determined from the bestfit regression between variables QT and RR: QTk ⫽ QT/RRk (k estimated at 0.354 for men, 0.338 for women). The association between various cardiovascular risk factors and the QTk duration was assessed by Spearman correlation coefficients, adjusted for age and other cardiovascular risk factors. The QTk interval was not related to heart rate (percentage of variation was equal to 0%, p ⬎0.3); because this rate correction index was close to 1⁄3, the 0002-9149/00/$–see front matter PII S0002-9149(00)01015-8
557
TABLE I Spearman Correlation Coefficients Adjusted on Age (p value), with Heart Rate and Heart Rate–Corrected QT Interval (QTk) in a Healthy Population of 1,395 Men and 1,499 Women from the DESIR Study Heart Rate Variables Body mass index Waist-hip ratio Systolic blood pressure Diastolic blood pressure Glucose HbA1c Insulin Cholesterol Triglycerides HDL cholesterol LDL cholesterol* Lipoprotein (a) Fibrinogen
QTk Interval
Men 0.06 (0.02) 0.17 (0.0001) 0.15 (0.0001) 0.15 (0.0001) 0.11 (0.0001) 0.12 (0.0001) 0.19 (0.0001) 0.1.1 (0.0001) 0.11 (0.0001) ⫺0.02 (0.4) 0.09 (0.0008) ⫺0.02 (0.5) 0.11 (0.0001)
Women 0.09 0.13 0.15 0.14 0.21 0.10 0.19 0.04 0.12 ⫺0.03 0.02 ⫺0.01 0.10
(0.0003) (0.0001) (0.0001) (0.0001) (0.0001) (0.0001) (0.0001) (0.09) (0.0001) (0.3) (0.6) (0.7) (0.0002)
Men ⫺0.01 (0.7) ⫺0.11 (0.0001) ⫺0.04 (0.2) ⫺0.05 (0.05) ⫺0.02 (0.4) ⫺0.09 (0.0006) ⫺0.09 (0.0007) 0.02 (0.4) ⫺0.07 (0.02) 0.06 (0.03) 0.002 (0.9) 0.04 (0.1) 0.004 (0.9)
Women ⫺0.01 (0.7) ⫺0.05 (0.07) 0.01 (0.7) ⫺0.01 (0.8) ⫺0.09 (0.0007) ⫺0.11 (0.0001) ⫺0.03 (0.3) ⫺0.03 (0.3) ⫺0.02 (0.5) ⫺0.003 (0.9) ⫺0.02 (0.4) ⫺0.06 (0.3) ⫺0.06 (0.03)
*Estimated by the Dahlen formula: total cholesterol HDL cholesterol ⫺ triglycerides/5 ⫺ (lipoprotein(a)/0.3). All variables are expressed in g/L. HDL ⫽ high-density lipoprotein; LDL ⫽ low-density lipoprotein.
result was similar for Fridericia’s formula (QTf ⫽ QT/RR1/3) (0%, p ⬎0.3). In contrast, the interval calculated by Bazett’s formula was correlated with heart rate (23%, p ⬍0.001). The men had on average a heart rate– corrected interval QTk of 376 ⫾ 18 ms. There was an inverse correlation between QTk and HbA1c (r ⫽ ⫺0.09, p ⬍0.001) and fasting insulin (r ⫽ ⫺0.09, p ⬍0.001) after adjusting for age (Table I) that remained significant only for HbA1c after adjustment on age, body mass index, systolic blood pressure, total cholesterol, and triglycerides. Heart rate was significantly correlated with most of the risk factors studied. In women (QTk ⫽ 382 ⫾ 17 ms), there was an inverse correlation between QTk and HbA1c (r ⫽ ⫺0.11, p ⬍0.001) and fasting plasma glucose (r ⫽ ⫺0.09, p ⬍0.001), and these results remained significant after adjustment of other parameters. Alcohol consumption did not affect the QTk duration in men or women. In men who smoked, the number of cigarettes smoked per day was positively correlated with the QTk duration (r ⫽ 0.14, p ⫽ 0.01 after adjustment on age). High physical activity was associated with an increase in QTk in men (381 ⫾ 7 vs 376 ⫾ 17 ms in men with moderate activity and 374 ⫾ 17 ms in men with low activity; overall p ⬍0.001). •••
Besides the large number of subjects, this study about the relations between QT duration and coronary artery disease risk factors had (1) an automatic measurement of the QT interval duration (with a high reproducibility and no inter- and intraobserver variability), and (2) used a specific heart rate– correction formula for the QT interval duration. One limitation of QT measurement in screening for risk stratification is the differences between observers in manually determining the end of the T wave.8,12–14 Recent findings have suggested that computer-determined QT intervals have a high reproducibility and may differentiate patients with hypertrophic cardiomyopathy from normal subjects, or may help predict cardiac mortality in 558 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 86
the elderly.6,15,16 Because of its relation to other risk factors and its independent prognostic value, heart rate is a confounder that may have an important role in predicting mortality by the QT interval. Thus, it was important to have an adequate correction formula for the present study to evaluate more precisely the relations between corrected QT duration and coronary artery disease risk factors. Previous studies have found that the heart rate– corrected QT interval has a prognostic value, independent of other cardiovascular risk indicators such as cigarette smoking, hypertension, lipid profile, body mass index, and diabetes mellitus.6 However, one of our major findings is that the heart rate– corrected QT duration may be in part directly influenced by some coronary risk factors (glucose homeostasis, physical activity, tobacco use). The glucose homeostasis parameters were inversely related to the QTk duration. These results, different from previous studies, could be related to the use of a different rate-correction formula. The increase in sympathetic activity and ventricular inotropism by insulin may explain our results. The effect of disturbed glucose metabolism on myocardial cells with changes in cation (sodium and potassium) transport and concentrations that may modify repolarization may be another explanation. Because of the relative shortening of the corrected QT interval with an increase in glucose, insulin, and HbA1c, the mechanism of an increased risk associated with an elevation of these latter parameters could be an association with a short refractory period along with a short excitation wavelength. This would predispose to reentry rather than an increased dispersion of repolarization or early afterdepolarization. These mechanisms were suggested to explain the increased risk of the lengthening of the QT interval with increasing cardiovascular risk factors.17 The increase in QTk duration with high physical activity may be explained by a possible higher left ventricular mass. To our knowledge, the positive relation between heart rate– corrected QT duration and tobacco use has not been SEPTEMBER 1, 2000
previously reported and could be related to ischemic myocardial damage or subclinical atherosclerosis, an explanation usually suggested for the longer corrected QT associated with other risk factors.18 Thus, after correcting for heart rate, the QT duration was influenced by glucose homeostasis, tobacco consumption (with a dose-effect relation in men), and physical activity in men. These findings may help to understand the mechanisms of sudden death in apparently healthy subjects. Acknowledgment: The hypotheses were formulated by Mat Labrunie, for a short thesis.
APPENDIX The DESIR Study Group: INSERM U258: B. Balkau, P. Ducimetie`re, E. Eschwe`ge; INSERM U367: F. Alhenc-Gelas; CHU d’Angers: A. Bechetoille, Y. Gallois, A. Girault; Hoˆpital Bichat: M. Marre; Association de Cardiologie du Centre, Val de Loire: M. Brochier; Centres d’Examens de Sante´ du Re´seau 9: Alenc¸on—M.C. Chesnier; Angers—F. Rabouin; Blois—J.M. Le Mauff, J.P. Sigalas; Caen—A. Caradec, C. Geslain; Chartres—D. Arondel; Chateauroux—M. Novak; Cholet—A. Petrella; Le Mans—A. D’Hour; Orle´ans—P. Le´pinay, E. Wilpart; Tours—B. Royer; Coordinateur Administratif du Re´seau 9: N. Verstraete; Institut de Recherche en Me´decine Ge´ne´rale: Basse-Normandie—Ph. Aubourg; Center—J. Cogneau, C. Rougeron; Pays de Loire—V. Diquero; Me´de´cins Ge´neralistes des De´partements; Institut Re´gional pour la Sante´: E. Cace`s, M. Cailleau, J.M. Jacquelin, J.G. Moreau, F. Rakotozafy, J. Tichet, S. Vol.
1. Moss AJ, Schwartz PJ, Crampton RS, Tzironi D, Locati EH, MacCluer J, Hall
WJ, Weitkamp L, Vincent GM, Garson A Jr., et al. The long QT syndrome. prospective longitudinal study of 328 families. Circulation 1991;84:1136 –1144. 2. Ahnve S. QT interval prolongation in acute myocardial infarction. Eur Heart J 1985;6(suppl D):85–95. 3. Schwartz PJ, Wolf S. QT interval prolongation as predictor of sudden death in patients with myocardial infarction. Circulation 1978;57:1074 –1077. 4. Bellavere F, Ferri M, Guarini L, Bax G, Piccoli A, Cardene C, Fedele D. Prolonged QT period in diabetic autonomic neuropathy: a possible role in sudden cardiac death? Br Heart J 1988;59:379 – 83.
5. Schouten EG, Dekker JM, Meppelink P, Kok EJ, Vandenbroucke JP, Pool J. QT-interval prolongation predicts cardiovascular mortality in an apparently healthy population. Circulation 1991;84:1516 –1523. 6. de Bruyne MC, Hoes AW, Kors JA, Hofman A, van Bemmel JH, Grobbee DE. Prolonged QT interval predicts cardiac and all-cause mortality in the elderly. The Rotterdam Study. Eur Heart J 1999;20:278 –284. 7. Dekker JM. The value of the heart-rate corrected QT-interval for cardiovascular risk stratification. Eur Heart J 1999;20:250 –251. 8. Dekker JM, Schouten EG, Klootwijk P, Pool J, Kromhout D. Association between QT interval and coronary heart disease in middle-aged and elderly men. The Zutphen Study. Circulation 1994;90:779 –785. 9. Goldberg RJ, Bengtson J, Chen ZY, Anderson KM, Locati E, Levy D. Duration of the QT interval and total and cardiovascular mortality in healthy persons (The Framingham Heart Study experience). Am J Cardiol 1991;67:55–58. 10. Dekker JM, Feskens EJ, Schouten EG, Klootwijk P, Pool J, Kromhout D. QTc duration is associated with levels of insulin and glucose intolerance. The Zutphen Elderly Study. Diabetes 1996;45:376 –380. 11. Mennen LI, Balkau B, Vol S, Caces E, Eschwege E. Fibrinogen: a possible link between alcohol consumption and cardiovascular disease? DESIR Study Group. Arterioscler Thromb Vasc Biol 1999;19:887– 892. 12. Willems JL, Abreu-Lima LC, Arnaud P, van Bemmell JM, Brohet C, Degani R, Denis B, Gehring J, Graham I, van Herpen G, et al. The diagnostic performance of computer programs for the interpretation of electrocardiograms. N Engl J Med 1991;325:1767–1773. 13. Willems JL, Arnaud P, van Bemmel JH, Bourdillon PJ, Brohet C, Dalla Volta S, Andersen JD, Pegani R, Denis B, Demeester M, et al. Assessment of the performance of electrocardiographic computer programs with the use of a reference data base. Circulation 1985;71:523–534. 14. de Bruyne MC, Hoes AW, Kors JA, Dekker JM, Hofman A, van Bemmel JH, Grobbee DE. Prolonged QT interval: a tricky diagnosis? Am J Cardiol 1997;80: 1300 –1304. 15. Savelieva I, Yi G, Guo X, Hnatkova K, Malik M. Agreement and reproducibility of automatic versus manual measurement of QT interval and QT dispersion. Am J Cardiol 1998;81:471– 477. 16. Savelieva I, Yap YG, Yi G, Guo X, Camm AJ, Malik M. Comparative reproducibility of QT, QT peak, and T peak-T end intervals and dispersion in normal subjects, patients with myocardial infarction, and patients with hypertrophic cardiomyopathy. Pacing Clin Electrophysiol 1998;21(11 Pt 2):2376 –2381. 17. Zipes DP. The Long QT Interval Syndrome. A Rosetta stone for sympathetic related ventricular tachyarrhythmias. Circulation 1991;84:1414 –1419. 18. Festa A, D’Agostino R Jr, Rautaharju P, O’Leary DH, Rewers M, Mykkanen L, Haffner SM. Is QT interval a marker of subclinical atherosclerosis in nondiabetic subjects? The Insulin Resistance Atherosclerosis Study (IRAS). Stroke 1999;30:1566 –1571.
Continuous Intravenous Diltiazem Infusion for Short-Term Ventricular Rate Control in Children Robert H. Pass,
MD,
Leonardo Liberman, MD, Majid Al-Fayaddh, and Allan J. Hordof, MD
iltiazem is a calcium channel antagonist that has been demonstrated to be effective in controlling the D ventricular rate in settings of atrial flutter and fibrillation in adults.1– 6 Use of this agent for this indication in children has not previously been described. Despite potentially favorable effects of calcium antagonists on the atrioventricular node, many of the available agents can have direct negative effects on ventricular function, and at least 1 is relatively contraindicated in young infants.7–9 From the Pediatric Arrhythmia Service-Division of Pediatric Cardiology, Babies and Children’s Hospital of New York, New York Presbyterian Medical Center, Columbia Campus, New York; and Division of Pediatric Cardiology, New York Presbyterian Medical Center-Cornell Campus, New York, New York. Dr. Pass’ address is: Babies and Children’s Hospital of New York, 3959 Broadway 2 North, New York, New York 10032-3784. E-mail: [email protected]. Manuscript received December 3, 1999; revised manuscript received and accepted March 13, 2000. ©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 86 September 1, 2000
MD,
Patrick Flynn,
MD,
We describe the use of diltiazem in a group of children with atrial arrhythmias for whom definitive therapy for their primary arrhythmia was necessarily, temporarily delayed. As the numbers of survivors of surgery for complex congenital heart disease increase, the numbers of patients with primary atrial arrhythmias will also increase, making appropriate acute management of this patient population increasingly important. •••
The records of all patients who received intravenous diltiazem for ventricular rate control from September 1995 to May 1999 at New York Presbyterian Hospital (Columbia and Cornell campuses) were reviewed with particular emphasis on drug efficacy and adverse effects. During that time period, 10 patients were treated with intravenous diltiazem. Table I reviews the ages, diagnoses (arrhythmic), and other salient information about patients included in this 0002-9149/00/$–see front matter PII S0002-9149(00)01016-X
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