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Cardiovascular disease in Chinese type 2 diabetic women is associated with a prolonged QTc interval
International Journal of Cardiology 76 (2000) 75–80 www.elsevier.com / locate / ijcard
Cardiovascular disease in Chinese type 2 diabetic women is associated with a prolonged QTc interval Gary T.C. Ko MBChB FRCPI*, Juliana C.N. Chan MD FRCP, Julian A.J.H. Critchley MD FRCP, Clive S. Cockram MD FRCP Department of Medicine and Therapeutics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, N.T., Hong Kong Received 21 January 2000; received in revised form 10 August 2000; accepted 4 September 2000
Abstract We studied the relationships between QT interval and cardiovascular disease status in 192 Chinese type 2 diabetic patients. Of these 192 subjects, 132 (68.8%) were women and 60 (31.2%) were men. The mean age (6S.D.) was 56.6612.9 years (range: 23–84, median: 58.0 years). Women had longer QTc interval compared to men (0.40260.030 s vs. 0.38760.026 s, P,0.01). Of the 192 subjects, 18 women and two men had prolonged QTc interval (QTc .0.433 s). Women with prolonged QTc interval have a 2.8-fold greater rate of cardiovascular disease as compared to those with normal QTc interval (38.9% vs. 14.0%, P,0.05). Using multiple regression analysis (stepwise) to assess the relationship with QTc interval with age, sex, body mass index, waist–hip ratio, blood pressure, fasting plasma glucose, glycated haemoglobin, lipid profiles, smoking and duration of diabetes as independent variables (R 2 5 0.146, F 58.88, P,0.001), systolic blood pressure ( b 50.198, P50.017), age ( b 50.189, P50.023) and female gender ( b 50.157, P50.037) were found to be independently associated with QTc interval. In conclusion, we have shown a significant association between prolonged QTc interval, ischaemic heart disease and cardiovascular disease in Chinese type 2 diabetic women. Age, systolic blood pressure and female gender are independently correlated to QTc interval. 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: QTc interval; Cardiovascular disease; Chinese; Diabetes mellitus
1. Introduction Diabetes mellitus carries significant morbidity and mortality [1,2]. The commonest cause of mortality in type 2 diabetic patients is cardiovascular disease [2,3]. In patients with ischaemic heart disease, the corrected QT (QTc) interval is more likely to be prolonged [4,5]. Also in patients with cerebrovascular accident, a prolonged QTc interval carried an in-
*Corresponding author. Tel.: 1852-2632-3131; fax: 1852-2689-2785. E-mail address: gtc [email protected] (G.T.C. Ko). ]
creased risk of mortality compared to a normal QTc interval [6]. QTc duration is significantly associated with insulin levels and glucose intolerance [7]. Veglio et al. have recently reported a significant correlation between QTc interval and ischaemic heart disease in type 1 diabetic patients [8]. Similar information in type 2 diabetic patients is, however, limited. In this cohort, we examined 192 Chinese type 2 diabetic patients and studied the relationships between their QTc interval and cardiovascular disease status. We also examined any potential risk factors for QTc prolongation in these patients.
0167-5273 / 00 / $ – see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 00 )00372-7
76
G.T.C. Ko et al. / International Journal of Cardiology 76 (2000) 75 – 80
2. Patients and methods
2.1. Subjects The present cohort involves 192 Chinese type 2 diabetic patients randomly recruited from the Diabetes Clinic, Prince of Wales Hospital, Hong Kong. The mean age (6S.D.) was 56.6612.9 years (range: 23–84, median: 58.0 years). The study was approved by the Ethical Committee, Prince of Wales Hospital, Hong Kong. All patients gave informed consent. On the study day, all patients attended after at least 12 h of fasting. Demographic data and past medical history were taken. Height and weight (measured to the nearest 0.1 kg) were measured with the subjects in light clothing and without shoes. Body mass index was calculated as the weight (kg) divided by the square of the height (m). Waist circumference was taken as the minimum circumference between the umbilicus and xiphoid process and measured to the nearest 0.5 cm. Hip circumference was measured as the maximum circumference around the buttocks posteriorly and the symphysis pubis anteriorly and measured to the nearest 0.5 cm. Waist–hip ratio was then calculated. After sitting for at least 5 min, blood pressure was measured in the right arm using a standard mercury sphygmomanometer. The Korotkoff sound V was taken as the diastolic blood pressure. The mean value of two readings measured 1 min apart was used. Cerebrovascular accident (CVA) was defined as either history of stroke with residual disability or stroke with full recovery. Ischaemic heart disease (IHD) was defined to be present if there was history of coronary angioplasty or coronary artery bypass graft surgery, or definite history of myocardial infarct requiring hospitalization, or confirmed coronary artery disease attending physician for treatment. Cardiovascular disease (CVSD) was defined as history of CVA and / or IHD. After the patient had rested in the supine position for 10 min, a standard resting 12-lead electrocardiogram (paper speed 25 mm / s) was performed. QT intervals were read from three leads: V2, V6, and I, II, or III, in whichever the longest QT interval was observed. In each lead, QT intervals and the preceding RR intervals of five non-consecutive sinus beats were measured to reduce measurement error and
because QT interval may slightly vary from beat to beat. The beginning of the QT interval was defined as the first deflection of the QRS complex. The end of the T wave was defined as the point of maximal change in the slope as the T wave merges with the baseline [7]. The QT interval corrected (QTc) for the cardiac cycle length was calculated according to Bazett’s formula: QTc5Q2T / [R2R] 1 / 2 [9]. QTc .0.433 s was defined as prolonged based on the relevance of this cut-off level with cardiac autonomic neuropathy in diabetic patients [10]. All electrocardiograms were measured by one physician who did not know the cardiovascular status of any of the subjects.
2.2. Laboratory investigations Blood was taken for measurement of fasting plasma glucose, glycated hemoglobin, total cholesterol, triglyceride, high-density lipoprotein cholesterol, renal / liver functions and calcium. Low-density lipoprotein cholesterol was calculated using the Friedewald’s formula [11]. Plasma glucose was measured by the hexokinase method (Hitachi 911 analyzer, Boehringer Mannheim, Mannheim, Germany). Glycated haemoglobin was measured by an automated ion-exchange chromatographic method (BioRad Laboratory, Hercules, CA, USA). Total cholesterol and triglyceride were assayed enzymatically with commercial reagents (Baker Instruments Corporation, Allentown, PA, USA) on a Cobas Mira analyzer (Hoffmann-La Roche, Basle, Switzerland). High-density lipoprotein and its subfractions were determined after fractional precipitation with dextran sulphate–MgCl 2 .
2.3. Statistical analysis Statistical analysis was performed using the SPSS (version 8.0) software on an IBM compatible computer. All results are expressed as mean6S.D. or n (%) where appropriate. The analysis of variance and chi-square test were used for two-group comparisons. Age and sex adjusted partial correlation coefficients between prolonged QTc, QTc interval and other clinical and biochemical characteristics were analyzed. Logistic regression analysis with age, body mass index, waist–hip ratio, blood pressure, fasting
G.T.C. Ko et al. / International Journal of Cardiology 76 (2000) 75 – 80
plasma glucose, glycated haemoglobin, lipid profiles, smoking, prolonged QTc (yes51, no50) and duration of diabetes as independent variables were performed to assess the risk of CVA, IHD and CVSD. Relative risk (RR) with 95% confidence interval was calculated. Multiple regression analysis (stepwise) with age, sex, body mass index, waist–hip ratio, blood pressure, fasting plasma glucose, glycated haemoglobin, lipid profiles, smoking and duration of diabetes as independent variables were performed to assess the relationship with QTc interval. A P value ,0.05 (two-tailed) was considered to be significant.
3. Results Of the 192 Chinese type 2 diabetic subjects, 132 (68.8%) were women and 60 (31.2%) were men. Table 1 summarizes their clinical characteristics. The males, as compared to the females, had more smokers, a higher waist–hip ratio, diastolic blood pressure and triglyceride concentration and lower high-density lipoprotein cholesterol concentration. Women had longer QTc interval as compared to men
77
(0.40260.030 s vs. 0.38760.026 s, P,0.01). All subjects had normal electrolyte levels. Of the 192 subjects, 18 women and two men had prolonged QTc interval (QTc.0.433 s). Clinical and biochemical characteristics of those with or without prolonged QTc interval are compared and summarised in Table 2. Women with prolonged QTc interval have 2.8-times the rate of cardiovascular disease and 4.6-times the rate of ischaemic heart disease as compared to those with normal QTc interval (38.9% vs. 14.0%, P,0.05 and 27.8% vs. 6.1%, P,0.05, respectively). Table 3 illustrates the QTc interval and rate of prolonged QTc in the 192 subjects with or without cerebrovascular accident, ischaemic heart disease or cardiovascular disease. Diabetic women with cardiovascular disease have three times the rate of prolonged QTc as compared to those without cardiovascular disease (30.4% vs. 10.1%, P,0.05). Table 4 summarizes the results of logistic regression analysis to assess risk of CVA, IHD or CVSD in men and women. Prolonged QTc was independently associated with CVA and CVSD in women. Female type 2 diabetic patients with prolonged QTc carried a 5.4–5.8-fold increased risk of having IHD or CVSD. In men, CVA was independently associated with age
Table 1 The clinical characteristics of 192 Chinese type 2 diabetic patients a
Age, years BMI b , kg / m 2 WHR Systolic BP, mmHg Diastolic BP, mmHg Heart rate, beats / min Fasting PG, mmol / l HbA 1c , % Total cholesterol, mmol / l Triglyceride, mmol / l HDL, mmol / l LDL, mmol / l Duration of DM, years Smoking, % QTc, s Prolonged QTc c , % Cerebrovascular accident, % Ischaemic heart disease, % Cardiovascular disease, % a
All (n5192)
Women (n5132)
Men (n560)
56.6612.9 25.263.7 0.8960.06 141625 82612 83613 9.763.8 8.3161.98 6.861.2 2.562.5 1.2760.37 4.661.0 7.365.9 16 (8.3) 0.39860.030 20 (10.4) 17 (8.9) 20 (10.4) 36 (18.8)
57.6613.5 25.263.8 0.8760.07 143625 81611 86615 9.563.6 8.2461.96 6.961.1 2.361.6 1.3360.36 4.761.0 7.665.8 4 (3.0) 0.40260.030 18 (13.6) 11 (8.3) 13 (9.8) 23 (17.4)
54.3611.3 25.263.4 0.9260.04*** 138626 85614* 81612 10.064.2 8.4862.04 6.761.3 3.163.7* 1.1560.36** 4.561.1 6.666.1 12 (20.0)*** 0.38760.026** 2 (3.3)* 6 (10.0) 7 (11.7) 13 (21.7)
P-values comparing men and women after adjustment for age: *,0.05, **,0.01, ***,0.001. BMI, body mass index; WHR, waist–hip ratio; BP, blood pressure; HbA 1c , glycated hemoglobin; HDL, high density lipoprotein; LDL, low density lipoprotein; DM, diabetes mellitus. c Prolonged QTc5QTc interval .0.433 s. b
G.T.C. Ko et al. / International Journal of Cardiology 76 (2000) 75 – 80
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Table 2 The clinical and biochemical characteristics of 192 Chinese type 2 diabetic subjects with or without prolonged QTc interval (.0.433 s)a Women (n5132)
Age, years BMI b , kg / m 2 WHR Systolic BP, mmHg Diastolic BP, mmHg Fasting PG, mmol / l HbA 1c , % Total cholesterol, mmol / l Triglyceride, mmol / l HDL, mmol / l LDL, mmol / l Duration of DM, years Smoking, % QTc, s CVA, % IHD, % CVSD, %
Men (n560)
Normal QTc (n5114)
Prolonged QTc (n518)
Normal QTc (n558)
Prolonged QTc (n52)
57.0613.5 25.463.9 0.8760.06 142625 81611 9.463.6 8.2461.97 6.961.1 2.361.7 1.3160.35 4.761.0 7.565.8 4 (3.5) 0.39460.021 9 (7.9) 7 (6.1) 16 (14.0)
61.4613.3 24.162.8 0.8860.08 149626 80611 10.363.6 8.2761.96 6.660.9 2.061.1 1.4160.38 4.461.0 8.366.3 0 0.45760.019*** 2 (11.1) 5 (27.8)** 7 (38.9)*
54.0611.3 25.263.5 0.9260.04 136624 85614 10.164.2 8.4862.07 6.761.4 3.163.8 1.1560.36 4.561.1 6.365.9 11 (19.0) 0.38560.025 6 (10.3) 8 (13.8) 13 (22.4)
63.5610.6 25.863.1 0.9660.08 19368** 10462 7.263.5 8.6061.27 7.060.8 2.161.4 1.1460.35 4.960.6 16.566.4* 1 (50.0) 0.44260.085** 0 0 0
a
P-values comparing normal QTc and prolonged QTc after adjustment for age: *,0.05, **,0.01, ***,0.001. BMI, body mass index; WHR, waist–hip ratio; BP, blood pressure; HbA 1c , glycated hemoglobin; HDL, high density lipoprotein; LDL, low density lipoprotein; DM, diabetes mellitus; CVA, cerebrovascular accident; IHD, ischaemic heart disease; CVSD, cardiovascular disease. b
and total cholesterol while CVSD was independently associated with age. Using multiple regression analysis (stepwise) to assess the relationship with QTc interval (continuous variable) with age, sex, body mass index, waist–hip ratio, blood pressure, fasting plasma glucose,
glycated haemoglobin, lipid profiles, smoking and duration of diabetes as independent variables (R 2 5 0.146, F 58.88, P,0.001), systolic blood pressure ( b 50.198, P50.017), age ( b 50.189, P50.023) and female gender ( b 50.157, P50.037) were found to be independently associated with QTc interval.
Table 3 QTc interval and rate of prolonged QTc in 192 Chinese type 2 diabetic patients with or without CVA, IHD or CVSD a
Total (n5192)
b
CVA IHD
CVSD Women (n5132)
CVA IHD CVSD
Men (n560)
CVA IHD CVSD
a b
Present (n517) Absent (n5175) Present (n520) Absent (n5172) Present (n536) Absent (n5156) Present (n511) Absent (n5121) Present (n512) Absent (n5120) Present (n523) Absent (n5109) Present (n56) Absent (n554) Present (n58) Absent (n552) Present (n513) Absent (n547)
P-values comparing presence and absence of CVA, IHD or CVSD: *,0.05, **,0.01. CVA, cerebrovascular accident; IHD, ischaemic heart disease; CVSD, cardiovascular disease.
QTc interval, s
Prolonged QTc, %
0.40060.025 0.39760.030 0.41160.033* 0.39660.029 0.40660.030 0.39660.030 0.40460.024 0.40260.031 0.42160.038* 0.40060.029 0.41360.032 0.40060.029 0.39260.027 0.38660.026 0.39660.019 0.38660.027 0.39360.022 0.38560.027
11.8 10.3 25.0* 8.7 19.4* 8.3 13.2 18.2 41.7** 10.8 30.4* 10.1 0 3.7 0 19.4 0 4.3
G.T.C. Ko et al. / International Journal of Cardiology 76 (2000) 75 – 80
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Table 4 Logistic regression analysis on the risk of CVA, IHD or CVSD with age, body mass index, waist–hip ratio, blood pressure, fasting plasma glucose, glycated haemoglobin, lipid profiles, smoking, prolonged QTc (yes51, no50) and duration of diabetes as independent variables in the 192 Chinese type 2 diabetic patients stratified according to sex
(a) Women (n5132) CVAa IHD CVSD (b) Men (n560) CVA IHD CVSD a
Independent variables entered into the model
b
S.E.
P-value
RR (95% CI)
Nil Prolonged QTc Prolonged QTc
– 1.754 1.695
– 0.667 0.591
– 0.009 0.004
–
Age Total cholesterol Nil Age
0.232 2.600 – 0.085
0.105 1.239 – 0.034
0.026 0.036 – 0.013
1.26 (1.03, 1.55) 13.47 (1.19, 152,69) – 1.09 (1.02, 1.16)
5.78 (1.56, 21.36) 5.44 (1.71, 17.34)
CVA, cerebrovascular accident; IHD, ischaemic heart disease; CVSD, cardiovascular disease.
4. Discussion QTc prolongation is associated with sudden death in patients with or without history of myocardial infarction [4,12]. Severe arrhythmia due to altered autonomic nervous system function has been suggested to be the major cause for the increased cardiac death in subjects with prolonged QTc interval [13]. Similarly, cardiac autonomic neuropathy resulting in sympathetic imbalance and QTc interval prolongation was believed to be the reason for the predisposition to sudden arrhythmia and death in diabetic patients [14,15]. However, evidence is accumulating, which suggests a positive association between QTc prolongation and atherosclerotic disease, and not only sudden death due to arrhythmia. Recently, Naas et al. reported that in patients newly diagnosed to have non-insulin-dependent diabetes mellitus who have no overt cardiac disease, QTc interval is an excellent predictor of cardiac death after a mean follow up of 10.3 years [16]. In addition, Sawicki et al. has shown that in insulin-dependent diabetic patients with nephropathy, QT prolongation is associated with an increased mortality risk that is independent of the presence of autonomic neuropathy [17]. The present study is the first in Chinese on the association between QTc prolongation and cardiovascular diseases. Our data suggest this association is similar between Chinese and Caucasians. The EURODIAB study on insulin-dependent diabetes mellitus has recently confirmed the independent relationship between QTc interval and ischaemic
heart disease [8]. In the present study, Chinese type 2 diabetic women with QTc prolongation have a fivefold higher risk of ischaemic heart disease or cardiovascular disease as compared to those with normal QTc interval. Similar condition is not shown in men and probably due to the low number of male subjects with QTc prolongation (n52). A difference between men and women is well known in the general population [18]. In accord with this, a significant higher QTc interval in women as compared to men was found in our present study with Chinese subjects as well as Caucasians in the EURODIAB study [8]. QTc prolongation is associated with glucose intolerance [7]. Dekker et al. demonstrated a significant association between QTc interval, fasting plasma glucose, insulin and C-peptide in non-diabetic elderly men who had no previous history of myocardial infarctions, and suggested QTc could be part of the insulin resistance syndrome [7]. On the other hand, Veglio et al. demonstrated an independent association between QTc interval and age, glycated haemoglobin and blood pressure in type 1 diabetic patients [8]. Previous studies in diabetic patients have attributed the increased risk of QTc prolongation to the presence of autonomic neuropathy. We do not have detailed information about neuropathy in subjects of the present study. It is possible that autonomic neuropathy may partly explain the QTc prolongation. Nevertheless, in the present study with Chinese subjects, we have demonstrated that the QTc interval is independently associated with age, systolic blood pressure and female gender. More study is required to
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G.T.C. Ko et al. / International Journal of Cardiology 76 (2000) 75 – 80
delineate the exact role of QTc interval in the complicated network involving pancreatic function, insulin sensitivity and cardiovascular risk. In conclusion, we have shown a significant association between prolonged QTc interval, ischaemic heart disease and cardiovascular disease in Chinese type 2 diabetic women. In addition, age, systolic blood pressure and female gender are independently correlated to QTc interval.
References [1] Semenkovich CF, Heinecke JW. The mystery of diabetes and atherosclerosis. Diabetes 1997;46:327–34. [2] Moss SE, Klein R, Klein BEK. Cause-specific mortality in a population-based study of diabetes. Am J Public Health 1991;81:1158–62. [3] Panzram G. Mortality and survival in type 2 diabetes mellitus. Diabetologia 1987;30:123–31. [4] Schwartz PJ, Wolf S. QT interval prolongation as predictor of sudden death in patients with myocardial infarction. Circulation 1978;57:1074–7. [5] Surawicz B, Knoebel SB. Long QT: good, bad or indifferent? J Am Coll Cardiol 1984;4:398–413. [6] Assmann I, Muller E. Prognostic significance of different QTintervals in the body surface ECG in patients with acute myocardial infarction and in patients with acute or chronic cerebral processes. Acta Cardiol 1990;45:501–4. [7] 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;45:376–80.
[8] Veglio M, Borra M, Stevens LK, Fuller JH, Perin PC. The relation between QTc interval prolongation and diabetic complications. The EURODIAB IDDM Complication Study Group. Diabetologia 1999;42:68–75. [9] Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920;7:353–70. [10] Gonin JM, Kadrofske MM, Schmaltz S, Bastyr EJ, Vinik AI. Corrected Q-T interval prolongation as diagnostic tool for assessment of cardiac autonomic neuropathy in diabetes mellitus. Diabetes Care 1990;13:68–71. [11] Friedewald WT, Levy RI, Frederickson DS. Estimation of plasma low density lipoprotein cholesterol concentration without the use of the preparative ultracentrifuge. Clin Chem 1972;18:499–512. [12] Algra A, Tijssen JG, Roelandt JR, Pool J, Lubsen J. QTc prolongation measured by standard 12-lead electrocardiography is an independent risk factor for sudden death due to cardiac arrest. Circulation 1991;83:1888–94. [13] Schwartz PJ, Stone HL. The role of the autonomic nervous system in sudden coronary death. Ann NY Acad Sci 1982;382:162–80. [14] Merdler A, Abinader EG, Flugelman MY, Kantner Y. Beta-blockade in asymptomatic diabetics with abnormal rest electrocardiograms. J Electrocardiol 1983;16:87–90. [15] Kahn JK, Sisson JC, Vinik AI. QT interval prolongation and sudden cardiac death in autonomic neuropathy. J Clin Endocrinol Metab 1987;64:751–4. [16] Naas AAO, Davidson NC, Thompson C, Cummings F, Ogston SA, Jung RT. QT and QTc dispersion are accurate predictors of cardiac death in newly diagnosed non-insulin dependent diabetes: cohort study. Br Med J 1998;316:745–6. [17] Sawicki PT, Dahne R, Bender R, Berger M. Prolonged QT interval as a predictor of mortality in diabetic nephropathy. Diabetologia 1996;39:77–81. [18] Cardiovascular Health Study Collaborative Research Group, Rautaharju PM, Manolio TA, Psaty BM, Borhani NO, Furberg CD. Correlates of QT prolongation in older adults (the Cardiovascular Health Study). Am J Cardiol 1994;73:999–1002.
Cardiovascular disease in Chinese type 2 diabetic women is associated with a prolonged QTc interval Gary T.C. Ko MBChB FRCPI*, Juliana C.N. Chan MD FRCP, Julian A.J.H. Critchley MD FRCP, Clive S. Cockram MD FRCP Department of Medicine and Therapeutics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, N.T., Hong Kong Received 21 January 2000; received in revised form 10 August 2000; accepted 4 September 2000
Abstract We studied the relationships between QT interval and cardiovascular disease status in 192 Chinese type 2 diabetic patients. Of these 192 subjects, 132 (68.8%) were women and 60 (31.2%) were men. The mean age (6S.D.) was 56.6612.9 years (range: 23–84, median: 58.0 years). Women had longer QTc interval compared to men (0.40260.030 s vs. 0.38760.026 s, P,0.01). Of the 192 subjects, 18 women and two men had prolonged QTc interval (QTc .0.433 s). Women with prolonged QTc interval have a 2.8-fold greater rate of cardiovascular disease as compared to those with normal QTc interval (38.9% vs. 14.0%, P,0.05). Using multiple regression analysis (stepwise) to assess the relationship with QTc interval with age, sex, body mass index, waist–hip ratio, blood pressure, fasting plasma glucose, glycated haemoglobin, lipid profiles, smoking and duration of diabetes as independent variables (R 2 5 0.146, F 58.88, P,0.001), systolic blood pressure ( b 50.198, P50.017), age ( b 50.189, P50.023) and female gender ( b 50.157, P50.037) were found to be independently associated with QTc interval. In conclusion, we have shown a significant association between prolonged QTc interval, ischaemic heart disease and cardiovascular disease in Chinese type 2 diabetic women. Age, systolic blood pressure and female gender are independently correlated to QTc interval. 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: QTc interval; Cardiovascular disease; Chinese; Diabetes mellitus
1. Introduction Diabetes mellitus carries significant morbidity and mortality [1,2]. The commonest cause of mortality in type 2 diabetic patients is cardiovascular disease [2,3]. In patients with ischaemic heart disease, the corrected QT (QTc) interval is more likely to be prolonged [4,5]. Also in patients with cerebrovascular accident, a prolonged QTc interval carried an in-
*Corresponding author. Tel.: 1852-2632-3131; fax: 1852-2689-2785. E-mail address: gtc [email protected] (G.T.C. Ko). ]
creased risk of mortality compared to a normal QTc interval [6]. QTc duration is significantly associated with insulin levels and glucose intolerance [7]. Veglio et al. have recently reported a significant correlation between QTc interval and ischaemic heart disease in type 1 diabetic patients [8]. Similar information in type 2 diabetic patients is, however, limited. In this cohort, we examined 192 Chinese type 2 diabetic patients and studied the relationships between their QTc interval and cardiovascular disease status. We also examined any potential risk factors for QTc prolongation in these patients.
0167-5273 / 00 / $ – see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 00 )00372-7
76
G.T.C. Ko et al. / International Journal of Cardiology 76 (2000) 75 – 80
2. Patients and methods
2.1. Subjects The present cohort involves 192 Chinese type 2 diabetic patients randomly recruited from the Diabetes Clinic, Prince of Wales Hospital, Hong Kong. The mean age (6S.D.) was 56.6612.9 years (range: 23–84, median: 58.0 years). The study was approved by the Ethical Committee, Prince of Wales Hospital, Hong Kong. All patients gave informed consent. On the study day, all patients attended after at least 12 h of fasting. Demographic data and past medical history were taken. Height and weight (measured to the nearest 0.1 kg) were measured with the subjects in light clothing and without shoes. Body mass index was calculated as the weight (kg) divided by the square of the height (m). Waist circumference was taken as the minimum circumference between the umbilicus and xiphoid process and measured to the nearest 0.5 cm. Hip circumference was measured as the maximum circumference around the buttocks posteriorly and the symphysis pubis anteriorly and measured to the nearest 0.5 cm. Waist–hip ratio was then calculated. After sitting for at least 5 min, blood pressure was measured in the right arm using a standard mercury sphygmomanometer. The Korotkoff sound V was taken as the diastolic blood pressure. The mean value of two readings measured 1 min apart was used. Cerebrovascular accident (CVA) was defined as either history of stroke with residual disability or stroke with full recovery. Ischaemic heart disease (IHD) was defined to be present if there was history of coronary angioplasty or coronary artery bypass graft surgery, or definite history of myocardial infarct requiring hospitalization, or confirmed coronary artery disease attending physician for treatment. Cardiovascular disease (CVSD) was defined as history of CVA and / or IHD. After the patient had rested in the supine position for 10 min, a standard resting 12-lead electrocardiogram (paper speed 25 mm / s) was performed. QT intervals were read from three leads: V2, V6, and I, II, or III, in whichever the longest QT interval was observed. In each lead, QT intervals and the preceding RR intervals of five non-consecutive sinus beats were measured to reduce measurement error and
because QT interval may slightly vary from beat to beat. The beginning of the QT interval was defined as the first deflection of the QRS complex. The end of the T wave was defined as the point of maximal change in the slope as the T wave merges with the baseline [7]. The QT interval corrected (QTc) for the cardiac cycle length was calculated according to Bazett’s formula: QTc5Q2T / [R2R] 1 / 2 [9]. QTc .0.433 s was defined as prolonged based on the relevance of this cut-off level with cardiac autonomic neuropathy in diabetic patients [10]. All electrocardiograms were measured by one physician who did not know the cardiovascular status of any of the subjects.
2.2. Laboratory investigations Blood was taken for measurement of fasting plasma glucose, glycated hemoglobin, total cholesterol, triglyceride, high-density lipoprotein cholesterol, renal / liver functions and calcium. Low-density lipoprotein cholesterol was calculated using the Friedewald’s formula [11]. Plasma glucose was measured by the hexokinase method (Hitachi 911 analyzer, Boehringer Mannheim, Mannheim, Germany). Glycated haemoglobin was measured by an automated ion-exchange chromatographic method (BioRad Laboratory, Hercules, CA, USA). Total cholesterol and triglyceride were assayed enzymatically with commercial reagents (Baker Instruments Corporation, Allentown, PA, USA) on a Cobas Mira analyzer (Hoffmann-La Roche, Basle, Switzerland). High-density lipoprotein and its subfractions were determined after fractional precipitation with dextran sulphate–MgCl 2 .
2.3. Statistical analysis Statistical analysis was performed using the SPSS (version 8.0) software on an IBM compatible computer. All results are expressed as mean6S.D. or n (%) where appropriate. The analysis of variance and chi-square test were used for two-group comparisons. Age and sex adjusted partial correlation coefficients between prolonged QTc, QTc interval and other clinical and biochemical characteristics were analyzed. Logistic regression analysis with age, body mass index, waist–hip ratio, blood pressure, fasting
G.T.C. Ko et al. / International Journal of Cardiology 76 (2000) 75 – 80
plasma glucose, glycated haemoglobin, lipid profiles, smoking, prolonged QTc (yes51, no50) and duration of diabetes as independent variables were performed to assess the risk of CVA, IHD and CVSD. Relative risk (RR) with 95% confidence interval was calculated. Multiple regression analysis (stepwise) with age, sex, body mass index, waist–hip ratio, blood pressure, fasting plasma glucose, glycated haemoglobin, lipid profiles, smoking and duration of diabetes as independent variables were performed to assess the relationship with QTc interval. A P value ,0.05 (two-tailed) was considered to be significant.
3. Results Of the 192 Chinese type 2 diabetic subjects, 132 (68.8%) were women and 60 (31.2%) were men. Table 1 summarizes their clinical characteristics. The males, as compared to the females, had more smokers, a higher waist–hip ratio, diastolic blood pressure and triglyceride concentration and lower high-density lipoprotein cholesterol concentration. Women had longer QTc interval as compared to men
77
(0.40260.030 s vs. 0.38760.026 s, P,0.01). All subjects had normal electrolyte levels. Of the 192 subjects, 18 women and two men had prolonged QTc interval (QTc.0.433 s). Clinical and biochemical characteristics of those with or without prolonged QTc interval are compared and summarised in Table 2. Women with prolonged QTc interval have 2.8-times the rate of cardiovascular disease and 4.6-times the rate of ischaemic heart disease as compared to those with normal QTc interval (38.9% vs. 14.0%, P,0.05 and 27.8% vs. 6.1%, P,0.05, respectively). Table 3 illustrates the QTc interval and rate of prolonged QTc in the 192 subjects with or without cerebrovascular accident, ischaemic heart disease or cardiovascular disease. Diabetic women with cardiovascular disease have three times the rate of prolonged QTc as compared to those without cardiovascular disease (30.4% vs. 10.1%, P,0.05). Table 4 summarizes the results of logistic regression analysis to assess risk of CVA, IHD or CVSD in men and women. Prolonged QTc was independently associated with CVA and CVSD in women. Female type 2 diabetic patients with prolonged QTc carried a 5.4–5.8-fold increased risk of having IHD or CVSD. In men, CVA was independently associated with age
Table 1 The clinical characteristics of 192 Chinese type 2 diabetic patients a
Age, years BMI b , kg / m 2 WHR Systolic BP, mmHg Diastolic BP, mmHg Heart rate, beats / min Fasting PG, mmol / l HbA 1c , % Total cholesterol, mmol / l Triglyceride, mmol / l HDL, mmol / l LDL, mmol / l Duration of DM, years Smoking, % QTc, s Prolonged QTc c , % Cerebrovascular accident, % Ischaemic heart disease, % Cardiovascular disease, % a
All (n5192)
Women (n5132)
Men (n560)
56.6612.9 25.263.7 0.8960.06 141625 82612 83613 9.763.8 8.3161.98 6.861.2 2.562.5 1.2760.37 4.661.0 7.365.9 16 (8.3) 0.39860.030 20 (10.4) 17 (8.9) 20 (10.4) 36 (18.8)
57.6613.5 25.263.8 0.8760.07 143625 81611 86615 9.563.6 8.2461.96 6.961.1 2.361.6 1.3360.36 4.761.0 7.665.8 4 (3.0) 0.40260.030 18 (13.6) 11 (8.3) 13 (9.8) 23 (17.4)
54.3611.3 25.263.4 0.9260.04*** 138626 85614* 81612 10.064.2 8.4862.04 6.761.3 3.163.7* 1.1560.36** 4.561.1 6.666.1 12 (20.0)*** 0.38760.026** 2 (3.3)* 6 (10.0) 7 (11.7) 13 (21.7)
P-values comparing men and women after adjustment for age: *,0.05, **,0.01, ***,0.001. BMI, body mass index; WHR, waist–hip ratio; BP, blood pressure; HbA 1c , glycated hemoglobin; HDL, high density lipoprotein; LDL, low density lipoprotein; DM, diabetes mellitus. c Prolonged QTc5QTc interval .0.433 s. b
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Table 2 The clinical and biochemical characteristics of 192 Chinese type 2 diabetic subjects with or without prolonged QTc interval (.0.433 s)a Women (n5132)
Age, years BMI b , kg / m 2 WHR Systolic BP, mmHg Diastolic BP, mmHg Fasting PG, mmol / l HbA 1c , % Total cholesterol, mmol / l Triglyceride, mmol / l HDL, mmol / l LDL, mmol / l Duration of DM, years Smoking, % QTc, s CVA, % IHD, % CVSD, %
Men (n560)
Normal QTc (n5114)
Prolonged QTc (n518)
Normal QTc (n558)
Prolonged QTc (n52)
57.0613.5 25.463.9 0.8760.06 142625 81611 9.463.6 8.2461.97 6.961.1 2.361.7 1.3160.35 4.761.0 7.565.8 4 (3.5) 0.39460.021 9 (7.9) 7 (6.1) 16 (14.0)
61.4613.3 24.162.8 0.8860.08 149626 80611 10.363.6 8.2761.96 6.660.9 2.061.1 1.4160.38 4.461.0 8.366.3 0 0.45760.019*** 2 (11.1) 5 (27.8)** 7 (38.9)*
54.0611.3 25.263.5 0.9260.04 136624 85614 10.164.2 8.4862.07 6.761.4 3.163.8 1.1560.36 4.561.1 6.365.9 11 (19.0) 0.38560.025 6 (10.3) 8 (13.8) 13 (22.4)
63.5610.6 25.863.1 0.9660.08 19368** 10462 7.263.5 8.6061.27 7.060.8 2.161.4 1.1460.35 4.960.6 16.566.4* 1 (50.0) 0.44260.085** 0 0 0
a
P-values comparing normal QTc and prolonged QTc after adjustment for age: *,0.05, **,0.01, ***,0.001. BMI, body mass index; WHR, waist–hip ratio; BP, blood pressure; HbA 1c , glycated hemoglobin; HDL, high density lipoprotein; LDL, low density lipoprotein; DM, diabetes mellitus; CVA, cerebrovascular accident; IHD, ischaemic heart disease; CVSD, cardiovascular disease. b
and total cholesterol while CVSD was independently associated with age. Using multiple regression analysis (stepwise) to assess the relationship with QTc interval (continuous variable) with age, sex, body mass index, waist–hip ratio, blood pressure, fasting plasma glucose,
glycated haemoglobin, lipid profiles, smoking and duration of diabetes as independent variables (R 2 5 0.146, F 58.88, P,0.001), systolic blood pressure ( b 50.198, P50.017), age ( b 50.189, P50.023) and female gender ( b 50.157, P50.037) were found to be independently associated with QTc interval.
Table 3 QTc interval and rate of prolonged QTc in 192 Chinese type 2 diabetic patients with or without CVA, IHD or CVSD a
Total (n5192)
b
CVA IHD
CVSD Women (n5132)
CVA IHD CVSD
Men (n560)
CVA IHD CVSD
a b
Present (n517) Absent (n5175) Present (n520) Absent (n5172) Present (n536) Absent (n5156) Present (n511) Absent (n5121) Present (n512) Absent (n5120) Present (n523) Absent (n5109) Present (n56) Absent (n554) Present (n58) Absent (n552) Present (n513) Absent (n547)
P-values comparing presence and absence of CVA, IHD or CVSD: *,0.05, **,0.01. CVA, cerebrovascular accident; IHD, ischaemic heart disease; CVSD, cardiovascular disease.
QTc interval, s
Prolonged QTc, %
0.40060.025 0.39760.030 0.41160.033* 0.39660.029 0.40660.030 0.39660.030 0.40460.024 0.40260.031 0.42160.038* 0.40060.029 0.41360.032 0.40060.029 0.39260.027 0.38660.026 0.39660.019 0.38660.027 0.39360.022 0.38560.027
11.8 10.3 25.0* 8.7 19.4* 8.3 13.2 18.2 41.7** 10.8 30.4* 10.1 0 3.7 0 19.4 0 4.3
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Table 4 Logistic regression analysis on the risk of CVA, IHD or CVSD with age, body mass index, waist–hip ratio, blood pressure, fasting plasma glucose, glycated haemoglobin, lipid profiles, smoking, prolonged QTc (yes51, no50) and duration of diabetes as independent variables in the 192 Chinese type 2 diabetic patients stratified according to sex
(a) Women (n5132) CVAa IHD CVSD (b) Men (n560) CVA IHD CVSD a
Independent variables entered into the model
b
S.E.
P-value
RR (95% CI)
Nil Prolonged QTc Prolonged QTc
– 1.754 1.695
– 0.667 0.591
– 0.009 0.004
–
Age Total cholesterol Nil Age
0.232 2.600 – 0.085
0.105 1.239 – 0.034
0.026 0.036 – 0.013
1.26 (1.03, 1.55) 13.47 (1.19, 152,69) – 1.09 (1.02, 1.16)
5.78 (1.56, 21.36) 5.44 (1.71, 17.34)
CVA, cerebrovascular accident; IHD, ischaemic heart disease; CVSD, cardiovascular disease.
4. Discussion QTc prolongation is associated with sudden death in patients with or without history of myocardial infarction [4,12]. Severe arrhythmia due to altered autonomic nervous system function has been suggested to be the major cause for the increased cardiac death in subjects with prolonged QTc interval [13]. Similarly, cardiac autonomic neuropathy resulting in sympathetic imbalance and QTc interval prolongation was believed to be the reason for the predisposition to sudden arrhythmia and death in diabetic patients [14,15]. However, evidence is accumulating, which suggests a positive association between QTc prolongation and atherosclerotic disease, and not only sudden death due to arrhythmia. Recently, Naas et al. reported that in patients newly diagnosed to have non-insulin-dependent diabetes mellitus who have no overt cardiac disease, QTc interval is an excellent predictor of cardiac death after a mean follow up of 10.3 years [16]. In addition, Sawicki et al. has shown that in insulin-dependent diabetic patients with nephropathy, QT prolongation is associated with an increased mortality risk that is independent of the presence of autonomic neuropathy [17]. The present study is the first in Chinese on the association between QTc prolongation and cardiovascular diseases. Our data suggest this association is similar between Chinese and Caucasians. The EURODIAB study on insulin-dependent diabetes mellitus has recently confirmed the independent relationship between QTc interval and ischaemic
heart disease [8]. In the present study, Chinese type 2 diabetic women with QTc prolongation have a fivefold higher risk of ischaemic heart disease or cardiovascular disease as compared to those with normal QTc interval. Similar condition is not shown in men and probably due to the low number of male subjects with QTc prolongation (n52). A difference between men and women is well known in the general population [18]. In accord with this, a significant higher QTc interval in women as compared to men was found in our present study with Chinese subjects as well as Caucasians in the EURODIAB study [8]. QTc prolongation is associated with glucose intolerance [7]. Dekker et al. demonstrated a significant association between QTc interval, fasting plasma glucose, insulin and C-peptide in non-diabetic elderly men who had no previous history of myocardial infarctions, and suggested QTc could be part of the insulin resistance syndrome [7]. On the other hand, Veglio et al. demonstrated an independent association between QTc interval and age, glycated haemoglobin and blood pressure in type 1 diabetic patients [8]. Previous studies in diabetic patients have attributed the increased risk of QTc prolongation to the presence of autonomic neuropathy. We do not have detailed information about neuropathy in subjects of the present study. It is possible that autonomic neuropathy may partly explain the QTc prolongation. Nevertheless, in the present study with Chinese subjects, we have demonstrated that the QTc interval is independently associated with age, systolic blood pressure and female gender. More study is required to
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delineate the exact role of QTc interval in the complicated network involving pancreatic function, insulin sensitivity and cardiovascular risk. In conclusion, we have shown a significant association between prolonged QTc interval, ischaemic heart disease and cardiovascular disease in Chinese type 2 diabetic women. In addition, age, systolic blood pressure and female gender are independently correlated to QTc interval.
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