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Insulin resistance is associated with hypertensive response to exercise in non-diabetic hypertensive patients
Diabetes Research and Clinical Practice 73 (2006) 65–69 www.elsevier.com/locate/diabres
Insulin resistance is associated with hypertensive response to exercise in non-diabetic hypertensive patients Sungha Park a,b,1, Jaemin Shim a,b,1, Jin-Bae Kim a,b, Young-Guk Ko a, Donghoon Choi a, Jong-Won Ha a, Se-Joong Rim a, Yangsoo Jang a,b,*, Namsik Chung a a
Division of Cardiology, Yonsei Cardiovascular Center, Yonsei University College of Medicine, SeodaemunGu 120-752, Seoul, South Korea b Cardiovascular Genome Center, Yonsei Cardiovascular Center, Yonsei University College of Medicine, Seoul, South Korea Received 20 July 2005; accepted 25 November 2005 Available online 4 January 2006
Abstract Aim: Insulin resistance is associated with increased sympathetic activity and elevated angiotensin II which may contribute to the excessive increase in arterial blood pressure during exercise. In this study, we hypothesized that increased insulin resistance will be significantly associated with hypertensive response to exercise (HRE) in non-diabetic hypertensive patients. Method: Two hundred seventy-five hypertensive patients were included in this study. HOMA-IR index using serum fasting glucose and insulin was calculated for insulin resistance. There were 79 patients with hypertensive response (age 56.1 9.4 years) and 196 patients without hypertensive response (age 53.9 8.9 years). Results: Insulin resistance, assessed by HOMA index, was significantly higher in hypertensive response group as compared to control (HOMA = 2.60 1.54 versus 1.76 0.86, P < 0.001). HOMA was an independent predictor of HRE when controlled for age, sex, BMI and baseline SBP (odds ratio = 2.008, P < 0.001). Also, HOMA was significantly correlated with the magnitude of SBP elevation controlled for age, sex, BMI and baseline SBP as well (b = 0.293, P < 0.001). In conclusion, this study shows that insulin resistance is a significant determinant of hypertensive response to exercise. Further studies to determine the prognostic significance of this finding is warranted. # 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Insulin resistance; Hypertension; Hypertensive response to exercise
1. Introduction Hypertensive response to exercise (HRE) is an adverse prognostic factor for future cardiovascular events [1–3]. Insulin resistance increases blood pressure through multiple mechanisms such as increased
* Corresponding author. Tel.: +82 2 2228 8455; fax: +82 2 393 2041. E-mail address: [email protected] (Y. Jang). 1 These authors contributed equally to this article.
sympathetic stimulation, increased renal sodium absorption, decreased insulin mediated vasodilation due to endothelial dysfunction and increased activation of the renin–angiotensin–alodsterone system and capillary rarefaction which may all contribute to the excessive increase in arterial blood pressure during exercise [4–9]. Previous studies have shown that increased blood pressure response during exercise in hypertensives are associated with adverse left ventricular remodeling and increased morbidity from myocardial infarction [10,11]. Therefore, clinical
0168-8227/$ – see front matter # 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2005.11.008
66
S. Park et al. / Diabetes Research and Clinical Practice 73 (2006) 65–69
determinants of hypertensive response in hypertensive patients may have significant clinical implications. To our knowledge, there has not been a previous study performed regarding the association of insulin resistance with hypertensive response to exercise in nondiabetic, hypertensive patients. Therefore, we hypothesized that increased insulin resistance will be significantly associated with hypertensive response to exercise in non-diabetic, treated hypertensive patients. 2. Methods The study subjects were 275 non-diabetic hypertensive patients being treated at Yonsei Cardiovascular Hospital between January of 2004 and April of 2005. Patients with treated blood pressure of <160/100 mmHg were enrolled in the study. At the time of initial enrollment, patients underwent a complete physical examination, a baseline electrocardiogram, and laboratory assessment. A hypertensive response to exercise was defined by maximum systolic BP 210 mmHg in males and 190 mmHg in females as described previously [3]. Patients with any of the following were excluded from participation: valvular heart disease; peripheral vascular disease; significant systemic disease; history of inflammatory disease; symptomatic cerebrovascular disease (including previous transient ischemic attack within 6 months); history of significant coronary artery disease; a clinically significant atrioventricular conduction disturbance; history of atrial fibrillation or other serious arrhythmia; history of congestive heart failure; liver cirrhosis; serum creatinine >1.4 mg/dl; history of diabetes mellitus (or fasting blood sugar of >126 mg/dl); pregnant women and women of childbearing potential who were not using an appropriate method of contraception were also excluded. Use of antihypertensive medications other than the study agents, lithium, major psychotropic agents, oral steroids, or daily non-steroidal anti-inflammatory drugs, high-dose acetylsalicylic acid, drugs with possible interactions with the study drug (digoxin, cimetidine, rifampin, erythromycin, itraconazole, grapefruit juice) was not permitted during the study. Fasting insulin level was determined by the immunoradiometric assay using gamma counter after the patient had fasted for 12 h overnight (Hewlett-Packard, USA). The coefficient of variation of insulin measurement was 2.1% for the intraobserver coefficient of variation (%) and 4.7% for the interobserver coefficient of variation (%). Insulin resistance was determined by calculating the HOMA-IR index, which is defined as [fasting blood glucose (mg/dl) serum fasting insulin (mIU/ml)/405] [12]. The study was approved beforehand by the institutional ethics committee and the procedures followed were in accordance with the institutional guidelines. Prior to the study, all participants submitted written informed consent. Symptom limited exercise test after taking hypertensive medication as usual was performed using the Bruce protocol [13]. The exercise was performed in four stages which were 3 min in duration.
Sphygmomanometric blood pressure was measured at baseline, at the end of each 3 min stage.
3. Statistical analysis Values were expressed as mean S.D. Comparison of the discrete variables was performed using the Chisquare analysis. Comparison of continuous variables with a normal distribution between the two study groups was performed using the Student’s t-test. If the distribution were skewed, non-parametric test was used. Independent predictors of blood pressure response during exercise were determined using the multiple linear regression analysis. Independent predictors of hypertensive response to exercise were determined using the logistic regression analysis. In multivariate analysis, body mass index (WHO Asian-Pacific guideline: <23, 23–25, >25 kg/m2), baseline systolic blood pressure (tertiles: <125, 125–135, >135 mg/dl), diastolic blood pressure (tertiles: <85, 85–95, >95 mg/dl), age (<52, 52–59, >59 years), low dense lipoprotein (<107, 108–131, >131 mg/dl), HOMA index (<1.41, 1.42–2.13, >2.14 mg/dl) of which the distribution was Table 1 Baseline characteristics
Age (years) Sex (M:F) Baseline BP SBP (mmHg) DBP (mmHg) Peak SBP (mmHg) Peak DBP (mmHg) Pressure increase SBP (mmHg) Pressure increase DBP (mmHg) METs Smoking (%) BMI (kg/m2) T.chol (mg/dl) TG (mg/dl) HDL (mg/dl) LDL (mg/dl) FBS (mg/dl) Serum insulin (mU/ml) HOMA index
HRE(+) (n = 79)
HRE( ) (n = 196)
56.1 9.4 38:41
53.9 8.9 106:90
P-valuea 0.127 0.369
136.8 14.2 85.5 13.3
130.1 14.1 85.8 10.7
<0.001 0.794
213.7 17.4 98.4 16.4 76.5 20.3
174.9 18.5 93.0 11.9 44.9 20.2
<0.001 0.020 <0.001
12.8 17.9
7.3 12.7
0.005
11.2 2.1 35 (44.3%) 25.7 3.1 202.7 38.6 159.2 123.3 47.0 10.7 126.7 34.1 93.2 13.1 11.0 5.4
12.1 1.6 0.07 78 (39.8%) 0.492 25.0 2.9 0.013 194.2 37.2 0.088 162.4 103.8 0.982 45.5 10.9 0.210 117.1 34.9 0.048 85.9 10.8 <0.001 8.3 3.8 <0.001
2.60 1.54
1.76 0.86 <0.001
Values are n (%) or mean S.D.; SBP, systolic blood pressure; DBP, diastolic blood pressure; METs, metabolic equivalents; BMI, body mass index; HDL, high density lipoprotein; LDL, low density lipoprotein; FBS, fasting blood sugar; HOMA, homeostatic model assessment. a If the distribution were skewed, non-parametric test was used.
S. Park et al. / Diabetes Research and Clinical Practice 73 (2006) 65–69
Fig. 1. The magnitude of SBP increase during exercise according to the tertile level of HOMA-IR; SBP, systolic blood pressure; HOMA index, homeostatic model assessment (tertile: <1.41, 1.42–2.13, >2.14 mg/dl).
skewed were treated as categorical variables. Statistical analysis was performed with SPSS 11.0 (SPSS Inc., Chicago, IL, USA). 4. Results There were 79 patients with HRE (56.1 9.4, M:F = 38:41) and 196 patients without HRE. There was no significant difference in clinical variables such as age, gender, smoking except of BMI. The peak SBP, DBP and the magnitude of pressure increase of SBP, DBP were all significantly higher in patients with HRE
67
(Table 1). Also, HOMA-IR was significantly higher for patients with HRE. The significant elevation of blood pressure and HOMA-IR was demonstrated regardless of gender and whether the baseline blood pressure was well controlled (<140/90 mmHg) or not. Magnitude of increase in SBP showed significant increment in patients with upper tertile level of HOMA-IR compared to the patients with the first and second tertile (P < 0.001, Fig. 1). Multiple regression analysis demonstrated that increased HOMA index was independently correlated with increasing SBP (b = 0.238, P < 0.001) and DBP (b = 0.190, P = 0.001) during exercise (Table 2). Multiple logistic regression analysis showed that increasing HOMA index, baseline SBP and increased LDL were independent determinants of hypertensive response to exercise in this study (Table 3). Table 3 Multiple logistic regression analysis for independent determinants of hypertensive response to exercise
HOMA index Baseline SBP LDL Male gender BMI Age
Odd ratio
P-value
2.01 1.66 1.19 0.79 1.39 1.19
<0.001 0.003 0.032 0.438 0.121 0.335
(1.386–2.926) (1.182–2.327) (0.837–1.686) (0.441–1.425) (0.917–2.091) (0.837–1.686)
SBP, baseline systolic blood pressure (tertiles: <125, 125–135, >135 mg/dl); DBP, diastolic blood pressure (<85, 85–95, >95 mg/ dl); LDL, low dense lipoprotein (<107, 108–131, >131 mg/dl); HOMA index, homeostatic model assessment (<1.41, 1.42–2.13, >2.14 mg/dl); age (<52, 52–59, >59 years).
Table 2 Multiple linear regression analysis for independent determinants of pressure increase in SBP and DBP Unstandardized coefficient
Standardized coefficient
P-value
2
Increase in SBP (adjusted R = 0.201) Male gender 15.99 3.67 Baseline SBP 7.47 1.61 HOMA index 7.21 1.78 Age 0.97 1.70 BMI 1.06 1.92 LDL 2.33 1.69 Smoking 1.42 3.68
0.33 0.26 0.24 0.03 0.03 0.08 0.03
<0.001 <0.001 <0.001 0.568 0.581 0.169 0.699
Increase in DBP (adjusted R2 = 0.201) Male gender Baseline DBP HOMA index Age BMI LDL Smoking
0.06 0.36 0.19 0.05 0.04 0.13 0.04
0.451 <0.001 0.001 0.403 0.566 0.027 0.626
1.69 2.23 6.51 1.09 3.48 1.08 0.88 1.05 0.67 1.17 2.28 1.03 1.09 2.25
SBP, baseline systolic blood pressure (tertiles: <125, 125–135, >135 mg/dl); DBP, diastolic blood pressure (<85, 85–95, >95 mg/dl), LDL, low dense lipoprotein (<107, 108–131, >131 mg/dl); HOMA index, homeostatic model assessment (<1.41, 1.42–2.13, >2.14 mg/dl); age (<52, 52–59, >59 years).
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S. Park et al. / Diabetes Research and Clinical Practice 73 (2006) 65–69
5. Discussion This study shows that HOMA index is associated with HRE, which means insulin resistance can be a significant determinant of HRE. To our best knowledge, this is the first study to demonstrate the association of insulin resistance with HRE in non-diabetic, hypertensive patients. Insulin resistance is associated with excessive increase in sympathetic activity, increased activation of the renin–angiotensin–aldosterone system, capillary rarefaction and endothelial dysfunction which may all contribute to increased blood pressure response during exercise [14,15]. Progressive increase in insulin resistance is significantly correlated with increasing endothelial dysfunction with therapies to modify insulin resistance being associated with improvement of endothelial function [16]. Endothelial dysfunction associated with increased insulin resistance may play an important role not in resting satus significantly but in impairment of peripheral vasodilation during exercise which may contribute to hypertensive response to exercise in this study [17]. Further studies to demonstrate the association of insulin resistance with impaired peripheral vasodilation during exercise is warranted. The hypertensive response was independent of the baseline blood pressure in this study population with insulin resistance being significantly associated with hypertensive response independent of blood pressure. It is the notable finding showing the significance of insulin resistance related to HRE and prognostic role of insulin resistance in hypertensive patients. In fact, although the patients with elevated SBP were significantly associated with positive hypertensive response to exercise (Table 3), the magnitude of systolic blood pressure elevation showed negative correlation with the baseline systolic blood pressure. This may be explained by the ‘‘law of the initial value’’, which explains the phenomenon of smaller reaction on stimulus for the higher initial level of the parameter [1,18]. Previous studies regarding the association of insulin resistance and hypertensive response to exercise had shown correlation of diastolic BP, but not systolic BP with insulin resistance. This phenomenon was explained as due to the complexity of the brachial artery pressure during exercise due to the frequency dependent transmission characteristics of the upper limb [15]. However, although the upper limb blood pressure may show discrepancy with central aortic pressure, brachial artery pressure during exercise is still determined by the changes in forearm vascular resistance which was demonstrated to show correlation
with the degree of insulin resistance [19]. The proportion of patients taking each class of drugs and the average number of antihypertensive medications were not different among the patients with or without HRE. Therefore, we believe that blood pressure medications did not confound the analysis of data in this study. In conclusion, this study shows that insulin resistance is a significant determinant of hypertensive response to exercise. Further studies to determine the prognostic significance of this finding are warranted. Acknowledgement This work was supported by a grant from the Ministry of Health and Welfare, the Republic of Korea (00-PJ6-PG5-23-0001). References [1] J. Filipovsky´, P. Ducimetie`re, M.E. Safar, Prognostic significance of exercise blood pressure and heart rate in middle aged men, Hypertension 20 (1992) 333–339. [2] R. Mundal, S.E. Kjeldsen, L. Sandvik, G. Erikssen, E. Thaulow, J. Erikssen, Exercise blood pressure predicts cardiovascular mortality in middle-aged men, Hypertension 24 (1994) 56–62. [3] P.M. Mottram, B. Haluska, S. Yuda, R. Leano, T.H. Marwick, Patients with a hypertensive response to exercise have impaired systolic function without diastolic dysfunction or left ventricular hypertrophy, J. Am. Coll. Cardiol. 43 (2004) 848–853. [4] M.F. Wilson, B.H. Sung, G.A. Pincomb, W.R. Lovallo, Exaggerated pressure response to exercise in men at risk for systemic hypertension, Am. J. Cardiol. 66 (1990) 731–736. [5] U.B. Andersen, M.H. Olsen, H. Dige-Petersen, H. Ibsen, Exercise blood pressure is related to insulin resistance in subjects with two hypertensive parents, Blood Press. 12 (2003) 314–318. [6] H. Isaksson, T. Cederholm, E. Jansson, A. Nygren, J. Ostergren, Therapy-resistant hypertension associated with central obesity, insulin resistance, and large muscle fibre area, Blood Press. 2 (1993) 46–52. [7] G.M. Reaven, H. Lithell, L. Landsberg, Hypertension and associated metabolic abnormalities—the role of insulin resistance and the sympathoadrenal system, N. Engl. J. Med. 334 (1996) 374–381. [8] S. Julius, T. Gudbrandsson, K. Jamerson, O. Andersson, The interconnection between sympathetics, microcirculation, and insulin resistance in hypertension, Blood Press. 1 (1992) 9–19. [9] H. Hirose, I. Saito, H. Kawabe, T. Saruta, Insulin resistance and hypertension: seven-year follow-up study in middle-aged Japanese men (the KEIO study), Hypertens. Res. 26 (2003) 795–800. [10] G. Ciuffetti, G. Schillaci, S. Innocente, R. Lombardini, L. Pasqualini, S. Notaristefano, et al., Capillary rarefaction and abnormal cardiovascular reactivity in hypertension, J. Hypertens. 21 (2003) 2297–2303. [11] L.M. Pierson, S.L. Bacon, A. Sherwood, A.L. Hinderliter, M. Babyak, E.C.D. Gullette, et al., Relationship between exercise systolic blood pressure and left ventricular geometry in over-
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[12]
[13]
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weight, mildly hypertensive patients, J. Hypertens. 22 (2004) 399–405. D.R. Matthews, J.P. Hosker, A.S. Rudenski, B.A. Naylor, D.F. Treacher, R.C. Turner, Homeostasis model assessment: insulin resistance and-cell function from fasting plasma glucose and insulin concentration in man, Diabetologia 28 (1985) 412–419. R.A. Bruce, Exercise testing of patients with coronary heart disease: principles and normal standards of evaluation, Ann. Clin. Res. 3 (1971) 323–332. L. Landsberg, Insulin-mediated sympathetic stimulation: role in the pathogenesis of obesity-related hypertension (or, how insulin affects blood pressure, and why), J. Hypertens. 19 (2001) 523–528. S.E. Brett, J.M. Ritter, P.J. Chowienczyk, Diastolic blood pressure changes during exercise positively correlate with serum
[16] [17]
[18] [19]
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cholesterol and insulin resistance, Circulation 101 (2000) 611– 615. W.A. Hsueh, C.J. Lyon, M.J. Quin˜ones, Insulin resistance and the endothelium, Am. J. Med. 117 (2004) 109–117. D.M. Gilligan, J.A. Panza, C.M. Kilcoyne, M.A. Waclawiw, P.R. Casino, A.A. Quyyumi, Contribution of endothelium-derived nitric oxide to exercise-induced vasodilation, Circulation 90 (1994) 2853–2858. J. Wilder, Stimulus and Response: The Law of Initial Value, John Wright & Sons, Bristol, England, 1967, pp. 10–84. E. Fossum, A. Høieggen, A. Moan, M. Rostrup, S.E. Kjeldsen, Insulin sensitivity is related to physical fitness and exercise blood pressure to structural vascular properties in young men, Hypertension 33 (1999) 781–786.
Insulin resistance is associated with hypertensive response to exercise in non-diabetic hypertensive patients Sungha Park a,b,1, Jaemin Shim a,b,1, Jin-Bae Kim a,b, Young-Guk Ko a, Donghoon Choi a, Jong-Won Ha a, Se-Joong Rim a, Yangsoo Jang a,b,*, Namsik Chung a a
Division of Cardiology, Yonsei Cardiovascular Center, Yonsei University College of Medicine, SeodaemunGu 120-752, Seoul, South Korea b Cardiovascular Genome Center, Yonsei Cardiovascular Center, Yonsei University College of Medicine, Seoul, South Korea Received 20 July 2005; accepted 25 November 2005 Available online 4 January 2006
Abstract Aim: Insulin resistance is associated with increased sympathetic activity and elevated angiotensin II which may contribute to the excessive increase in arterial blood pressure during exercise. In this study, we hypothesized that increased insulin resistance will be significantly associated with hypertensive response to exercise (HRE) in non-diabetic hypertensive patients. Method: Two hundred seventy-five hypertensive patients were included in this study. HOMA-IR index using serum fasting glucose and insulin was calculated for insulin resistance. There were 79 patients with hypertensive response (age 56.1 9.4 years) and 196 patients without hypertensive response (age 53.9 8.9 years). Results: Insulin resistance, assessed by HOMA index, was significantly higher in hypertensive response group as compared to control (HOMA = 2.60 1.54 versus 1.76 0.86, P < 0.001). HOMA was an independent predictor of HRE when controlled for age, sex, BMI and baseline SBP (odds ratio = 2.008, P < 0.001). Also, HOMA was significantly correlated with the magnitude of SBP elevation controlled for age, sex, BMI and baseline SBP as well (b = 0.293, P < 0.001). In conclusion, this study shows that insulin resistance is a significant determinant of hypertensive response to exercise. Further studies to determine the prognostic significance of this finding is warranted. # 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Insulin resistance; Hypertension; Hypertensive response to exercise
1. Introduction Hypertensive response to exercise (HRE) is an adverse prognostic factor for future cardiovascular events [1–3]. Insulin resistance increases blood pressure through multiple mechanisms such as increased
* Corresponding author. Tel.: +82 2 2228 8455; fax: +82 2 393 2041. E-mail address: [email protected] (Y. Jang). 1 These authors contributed equally to this article.
sympathetic stimulation, increased renal sodium absorption, decreased insulin mediated vasodilation due to endothelial dysfunction and increased activation of the renin–angiotensin–alodsterone system and capillary rarefaction which may all contribute to the excessive increase in arterial blood pressure during exercise [4–9]. Previous studies have shown that increased blood pressure response during exercise in hypertensives are associated with adverse left ventricular remodeling and increased morbidity from myocardial infarction [10,11]. Therefore, clinical
0168-8227/$ – see front matter # 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2005.11.008
66
S. Park et al. / Diabetes Research and Clinical Practice 73 (2006) 65–69
determinants of hypertensive response in hypertensive patients may have significant clinical implications. To our knowledge, there has not been a previous study performed regarding the association of insulin resistance with hypertensive response to exercise in nondiabetic, hypertensive patients. Therefore, we hypothesized that increased insulin resistance will be significantly associated with hypertensive response to exercise in non-diabetic, treated hypertensive patients. 2. Methods The study subjects were 275 non-diabetic hypertensive patients being treated at Yonsei Cardiovascular Hospital between January of 2004 and April of 2005. Patients with treated blood pressure of <160/100 mmHg were enrolled in the study. At the time of initial enrollment, patients underwent a complete physical examination, a baseline electrocardiogram, and laboratory assessment. A hypertensive response to exercise was defined by maximum systolic BP 210 mmHg in males and 190 mmHg in females as described previously [3]. Patients with any of the following were excluded from participation: valvular heart disease; peripheral vascular disease; significant systemic disease; history of inflammatory disease; symptomatic cerebrovascular disease (including previous transient ischemic attack within 6 months); history of significant coronary artery disease; a clinically significant atrioventricular conduction disturbance; history of atrial fibrillation or other serious arrhythmia; history of congestive heart failure; liver cirrhosis; serum creatinine >1.4 mg/dl; history of diabetes mellitus (or fasting blood sugar of >126 mg/dl); pregnant women and women of childbearing potential who were not using an appropriate method of contraception were also excluded. Use of antihypertensive medications other than the study agents, lithium, major psychotropic agents, oral steroids, or daily non-steroidal anti-inflammatory drugs, high-dose acetylsalicylic acid, drugs with possible interactions with the study drug (digoxin, cimetidine, rifampin, erythromycin, itraconazole, grapefruit juice) was not permitted during the study. Fasting insulin level was determined by the immunoradiometric assay using gamma counter after the patient had fasted for 12 h overnight (Hewlett-Packard, USA). The coefficient of variation of insulin measurement was 2.1% for the intraobserver coefficient of variation (%) and 4.7% for the interobserver coefficient of variation (%). Insulin resistance was determined by calculating the HOMA-IR index, which is defined as [fasting blood glucose (mg/dl) serum fasting insulin (mIU/ml)/405] [12]. The study was approved beforehand by the institutional ethics committee and the procedures followed were in accordance with the institutional guidelines. Prior to the study, all participants submitted written informed consent. Symptom limited exercise test after taking hypertensive medication as usual was performed using the Bruce protocol [13]. The exercise was performed in four stages which were 3 min in duration.
Sphygmomanometric blood pressure was measured at baseline, at the end of each 3 min stage.
3. Statistical analysis Values were expressed as mean S.D. Comparison of the discrete variables was performed using the Chisquare analysis. Comparison of continuous variables with a normal distribution between the two study groups was performed using the Student’s t-test. If the distribution were skewed, non-parametric test was used. Independent predictors of blood pressure response during exercise were determined using the multiple linear regression analysis. Independent predictors of hypertensive response to exercise were determined using the logistic regression analysis. In multivariate analysis, body mass index (WHO Asian-Pacific guideline: <23, 23–25, >25 kg/m2), baseline systolic blood pressure (tertiles: <125, 125–135, >135 mg/dl), diastolic blood pressure (tertiles: <85, 85–95, >95 mg/dl), age (<52, 52–59, >59 years), low dense lipoprotein (<107, 108–131, >131 mg/dl), HOMA index (<1.41, 1.42–2.13, >2.14 mg/dl) of which the distribution was Table 1 Baseline characteristics
Age (years) Sex (M:F) Baseline BP SBP (mmHg) DBP (mmHg) Peak SBP (mmHg) Peak DBP (mmHg) Pressure increase SBP (mmHg) Pressure increase DBP (mmHg) METs Smoking (%) BMI (kg/m2) T.chol (mg/dl) TG (mg/dl) HDL (mg/dl) LDL (mg/dl) FBS (mg/dl) Serum insulin (mU/ml) HOMA index
HRE(+) (n = 79)
HRE( ) (n = 196)
56.1 9.4 38:41
53.9 8.9 106:90
P-valuea 0.127 0.369
136.8 14.2 85.5 13.3
130.1 14.1 85.8 10.7
<0.001 0.794
213.7 17.4 98.4 16.4 76.5 20.3
174.9 18.5 93.0 11.9 44.9 20.2
<0.001 0.020 <0.001
12.8 17.9
7.3 12.7
0.005
11.2 2.1 35 (44.3%) 25.7 3.1 202.7 38.6 159.2 123.3 47.0 10.7 126.7 34.1 93.2 13.1 11.0 5.4
12.1 1.6 0.07 78 (39.8%) 0.492 25.0 2.9 0.013 194.2 37.2 0.088 162.4 103.8 0.982 45.5 10.9 0.210 117.1 34.9 0.048 85.9 10.8 <0.001 8.3 3.8 <0.001
2.60 1.54
1.76 0.86 <0.001
Values are n (%) or mean S.D.; SBP, systolic blood pressure; DBP, diastolic blood pressure; METs, metabolic equivalents; BMI, body mass index; HDL, high density lipoprotein; LDL, low density lipoprotein; FBS, fasting blood sugar; HOMA, homeostatic model assessment. a If the distribution were skewed, non-parametric test was used.
S. Park et al. / Diabetes Research and Clinical Practice 73 (2006) 65–69
Fig. 1. The magnitude of SBP increase during exercise according to the tertile level of HOMA-IR; SBP, systolic blood pressure; HOMA index, homeostatic model assessment (tertile: <1.41, 1.42–2.13, >2.14 mg/dl).
skewed were treated as categorical variables. Statistical analysis was performed with SPSS 11.0 (SPSS Inc., Chicago, IL, USA). 4. Results There were 79 patients with HRE (56.1 9.4, M:F = 38:41) and 196 patients without HRE. There was no significant difference in clinical variables such as age, gender, smoking except of BMI. The peak SBP, DBP and the magnitude of pressure increase of SBP, DBP were all significantly higher in patients with HRE
67
(Table 1). Also, HOMA-IR was significantly higher for patients with HRE. The significant elevation of blood pressure and HOMA-IR was demonstrated regardless of gender and whether the baseline blood pressure was well controlled (<140/90 mmHg) or not. Magnitude of increase in SBP showed significant increment in patients with upper tertile level of HOMA-IR compared to the patients with the first and second tertile (P < 0.001, Fig. 1). Multiple regression analysis demonstrated that increased HOMA index was independently correlated with increasing SBP (b = 0.238, P < 0.001) and DBP (b = 0.190, P = 0.001) during exercise (Table 2). Multiple logistic regression analysis showed that increasing HOMA index, baseline SBP and increased LDL were independent determinants of hypertensive response to exercise in this study (Table 3). Table 3 Multiple logistic regression analysis for independent determinants of hypertensive response to exercise
HOMA index Baseline SBP LDL Male gender BMI Age
Odd ratio
P-value
2.01 1.66 1.19 0.79 1.39 1.19
<0.001 0.003 0.032 0.438 0.121 0.335
(1.386–2.926) (1.182–2.327) (0.837–1.686) (0.441–1.425) (0.917–2.091) (0.837–1.686)
SBP, baseline systolic blood pressure (tertiles: <125, 125–135, >135 mg/dl); DBP, diastolic blood pressure (<85, 85–95, >95 mg/ dl); LDL, low dense lipoprotein (<107, 108–131, >131 mg/dl); HOMA index, homeostatic model assessment (<1.41, 1.42–2.13, >2.14 mg/dl); age (<52, 52–59, >59 years).
Table 2 Multiple linear regression analysis for independent determinants of pressure increase in SBP and DBP Unstandardized coefficient
Standardized coefficient
P-value
2
Increase in SBP (adjusted R = 0.201) Male gender 15.99 3.67 Baseline SBP 7.47 1.61 HOMA index 7.21 1.78 Age 0.97 1.70 BMI 1.06 1.92 LDL 2.33 1.69 Smoking 1.42 3.68
0.33 0.26 0.24 0.03 0.03 0.08 0.03
<0.001 <0.001 <0.001 0.568 0.581 0.169 0.699
Increase in DBP (adjusted R2 = 0.201) Male gender Baseline DBP HOMA index Age BMI LDL Smoking
0.06 0.36 0.19 0.05 0.04 0.13 0.04
0.451 <0.001 0.001 0.403 0.566 0.027 0.626
1.69 2.23 6.51 1.09 3.48 1.08 0.88 1.05 0.67 1.17 2.28 1.03 1.09 2.25
SBP, baseline systolic blood pressure (tertiles: <125, 125–135, >135 mg/dl); DBP, diastolic blood pressure (<85, 85–95, >95 mg/dl), LDL, low dense lipoprotein (<107, 108–131, >131 mg/dl); HOMA index, homeostatic model assessment (<1.41, 1.42–2.13, >2.14 mg/dl); age (<52, 52–59, >59 years).
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5. Discussion This study shows that HOMA index is associated with HRE, which means insulin resistance can be a significant determinant of HRE. To our best knowledge, this is the first study to demonstrate the association of insulin resistance with HRE in non-diabetic, hypertensive patients. Insulin resistance is associated with excessive increase in sympathetic activity, increased activation of the renin–angiotensin–aldosterone system, capillary rarefaction and endothelial dysfunction which may all contribute to increased blood pressure response during exercise [14,15]. Progressive increase in insulin resistance is significantly correlated with increasing endothelial dysfunction with therapies to modify insulin resistance being associated with improvement of endothelial function [16]. Endothelial dysfunction associated with increased insulin resistance may play an important role not in resting satus significantly but in impairment of peripheral vasodilation during exercise which may contribute to hypertensive response to exercise in this study [17]. Further studies to demonstrate the association of insulin resistance with impaired peripheral vasodilation during exercise is warranted. The hypertensive response was independent of the baseline blood pressure in this study population with insulin resistance being significantly associated with hypertensive response independent of blood pressure. It is the notable finding showing the significance of insulin resistance related to HRE and prognostic role of insulin resistance in hypertensive patients. In fact, although the patients with elevated SBP were significantly associated with positive hypertensive response to exercise (Table 3), the magnitude of systolic blood pressure elevation showed negative correlation with the baseline systolic blood pressure. This may be explained by the ‘‘law of the initial value’’, which explains the phenomenon of smaller reaction on stimulus for the higher initial level of the parameter [1,18]. Previous studies regarding the association of insulin resistance and hypertensive response to exercise had shown correlation of diastolic BP, but not systolic BP with insulin resistance. This phenomenon was explained as due to the complexity of the brachial artery pressure during exercise due to the frequency dependent transmission characteristics of the upper limb [15]. However, although the upper limb blood pressure may show discrepancy with central aortic pressure, brachial artery pressure during exercise is still determined by the changes in forearm vascular resistance which was demonstrated to show correlation
with the degree of insulin resistance [19]. The proportion of patients taking each class of drugs and the average number of antihypertensive medications were not different among the patients with or without HRE. Therefore, we believe that blood pressure medications did not confound the analysis of data in this study. In conclusion, this study shows that insulin resistance is a significant determinant of hypertensive response to exercise. Further studies to determine the prognostic significance of this finding are warranted. Acknowledgement This work was supported by a grant from the Ministry of Health and Welfare, the Republic of Korea (00-PJ6-PG5-23-0001). References [1] J. Filipovsky´, P. Ducimetie`re, M.E. Safar, Prognostic significance of exercise blood pressure and heart rate in middle aged men, Hypertension 20 (1992) 333–339. [2] R. Mundal, S.E. Kjeldsen, L. Sandvik, G. Erikssen, E. Thaulow, J. Erikssen, Exercise blood pressure predicts cardiovascular mortality in middle-aged men, Hypertension 24 (1994) 56–62. [3] P.M. Mottram, B. Haluska, S. Yuda, R. Leano, T.H. Marwick, Patients with a hypertensive response to exercise have impaired systolic function without diastolic dysfunction or left ventricular hypertrophy, J. Am. Coll. Cardiol. 43 (2004) 848–853. [4] M.F. Wilson, B.H. Sung, G.A. Pincomb, W.R. Lovallo, Exaggerated pressure response to exercise in men at risk for systemic hypertension, Am. J. Cardiol. 66 (1990) 731–736. [5] U.B. Andersen, M.H. Olsen, H. Dige-Petersen, H. Ibsen, Exercise blood pressure is related to insulin resistance in subjects with two hypertensive parents, Blood Press. 12 (2003) 314–318. [6] H. Isaksson, T. Cederholm, E. Jansson, A. Nygren, J. Ostergren, Therapy-resistant hypertension associated with central obesity, insulin resistance, and large muscle fibre area, Blood Press. 2 (1993) 46–52. [7] G.M. Reaven, H. Lithell, L. Landsberg, Hypertension and associated metabolic abnormalities—the role of insulin resistance and the sympathoadrenal system, N. Engl. J. Med. 334 (1996) 374–381. [8] S. Julius, T. Gudbrandsson, K. Jamerson, O. Andersson, The interconnection between sympathetics, microcirculation, and insulin resistance in hypertension, Blood Press. 1 (1992) 9–19. [9] H. Hirose, I. Saito, H. Kawabe, T. Saruta, Insulin resistance and hypertension: seven-year follow-up study in middle-aged Japanese men (the KEIO study), Hypertens. Res. 26 (2003) 795–800. [10] G. Ciuffetti, G. Schillaci, S. Innocente, R. Lombardini, L. Pasqualini, S. Notaristefano, et al., Capillary rarefaction and abnormal cardiovascular reactivity in hypertension, J. Hypertens. 21 (2003) 2297–2303. [11] L.M. Pierson, S.L. Bacon, A. Sherwood, A.L. Hinderliter, M. Babyak, E.C.D. Gullette, et al., Relationship between exercise systolic blood pressure and left ventricular geometry in over-
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