Increased sympathetic nervous system activity in Chinese hypertensive patients with type II diabetes mellitus

InternationalJournal of Cardiology50 (1995)69-74

ELSEVIER

Increased sympathetic nervous system activity in Chinese hypertensive patients with type II diabetes mellitus Paul Chan*a’b, C.W. Wang’,

T.S. Lina, C.W. Tsaia, W.H. Pand

aDepartment of Medicine, Taipei Municipal Chung Hsiao Hospital, Taipei, Taiwan bInslitute of Clinical Medicine of National Yang Ming University, Taipei, Taiwan ‘Department of Medicine, Taipei Municipal Jen Ai Hospital, Taipei, Taiwan ‘Instilute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

Received12December1994;revisionaccepted24 February1995

Abstract

To evaluate the coexistenceof sympathetic overactivity and hypertension in type 2 diabetic patients, a populationbasedstudy was conducted of newly-diagnosed type 2 diabetic patients recruited from a single community located at northern Taiwan. This study included 2877 (male 1382,female 1495)middle-aged ethnic Chinese adults, aged 45-65 years. Of the 1382males, 67 had newly-diagnosed type 2 diabetes mellitus, whereas 75 of the 1495femaleshad type 2 diabetes. The data showed that about 39% of diabetic patients had borderline hypertension (mean blood pressure 141/91mmHg) whereasthe averageincidence in non-diabetic subjectswas 15.5%.The borderline hypertensive diabetic patients had significantly higher heart rates (mean 78.8 vs. 69.3 beats/min; P < 0.001) than control subjects.However, the cardiac index was similar in both control and diabetic subjects (mean 2.48 vs. 2.53 l/min/m2; P > 0.05). Our data show that sympathetic overactivity and increased incidence of hypertension actually existed in these type 2 diabetic patients of Chinese origin. Keywords: Coronary artery disease;Risk factor; Sympathetic overactivity; Hypertension; Type 2 diabetes mellitus

1. Introduction Hypertension is a well defined major risk factor for stroke, cardiovascular disease,and death from cardiovascular causes [l]. Experience shows that there is no such thing as mild or borderline hypertension; this condition is a serious risk factor for * Corresponding author,No. 87, Tung Teh Road, Nan Kang, Taipei, Taiwan 115.

cardiovascular death. Confirmation of this aspect is proved after the publication of the Fifth Joint National Committee (JNC V) report [2], new US criteria for the diagnosis of hypertension that apply to all ages. Hypertension, according to this guideline, is diagnosed for consistent systolic blood pressure readings > 140 mmHg or/and diastolic readings > 90 mmHg in all adults. The Tecumseh study explores further the idea that essential hypertension is not a homogeneous

0167~5273/95/$09.500 1995Elsevier Science Ireland Ltd. All rights reserved SSDI 0167-5273(95)02321-C

IO

P. Chan et al. /International

Journal

disease that various biochemical, psychological and hemodynamic measurements may help to define distinct subtypes of hypertension [3,4]. Sympathetic overactivity, seenin the early phase of hypertension, is a well-recognised phenomenon and a large proportion of young, predominantly male patients with borderline hypertension have increased cardiac output and high heart rate [5-lo]. Sympathetic activation and increased catecholamine production has also been noted in diabetic patients [ll]. In subjects with type 2 diabetes, hypertension occurs about twice as frequently as in non-diabetics [12]. This study investigated the phenomenon of sympathetic overactivity and associatedhypertension in type 2 (non-insulin-dependent), diabetic patients in a middle-aged Chinese cohort. This study first showedthat sympathetic overactivity and associated borderline hypertension are commonly present in middle-aged Chinese diabetics. 2. Materials and metbods The Cardiovascular Disease Risk Factor Twotownship Study (CVDFACTS) is a longitudinal study, ongoing in two suburban communities: Chu-Dung (northwest Taiwan) and Pu-Tzu (southwest Taiwan). It was organized by the Academia Sinica, and supported by the Department of Health, Taiwan. This CVDFACTS focuseson the evolution of cardiovascular disease risk factors. The participants have been described in detail in a previous report [13]. The study was carried out on 2877 subjects (1382 men, 1495 women), whose ages ranged from 45 to 65 years. All the subjects were recruited from the same cohort located in northern Taiwan, Of the 1382 males, 67 (4.85%) had newly-diagnosed type 2 (non-insulin-dependent) diabetesmellitus, whereas the 1495 females had included 75 (5.02%) newlydiagnosed diabetics. For the 142 patients with diabetes mellitus, about 39% had borderline hypertension (mean 141/91mmHg). Besides collecting such baseline demographic data as height and body weight, venous blood was drawn after an overnight fast for determination of levels of plasma insulin, glucose, lipids, and elec-

of Cardiology 50 (1995) 69-74

trolytes. Informed consent was obtained from each subject, and the protocol conforms to guidelines of the 1975Declaration of Helsinski and was also approved by the Human ResearchCommittee of the Academia Sinica. Fasting glucose, cholesterol, triglyceride, uric acid, blood urea nitrogen, and creatinine levels were measured, using a Monarch Autoanalyzer System (Instrumental Laboratory, Lexington, TX, USA). EDTA-containing plasma was usedto quantify insulin level by the SERENO Insulin MAIA kit (ARES-Sereno Diagnostici SPA, Milan, Italy). Blood pressure was determined with a noninvasive blood pressuremonitor (Invivo Reserach Laboratories, Inc., Broken Arrow, OK, USA). Subjectshad been sitting for at least 10 min before their blood pressure was measured consecutively three times, with 30-s pulse measured in between. Repeatedmeasurementswere done at different occasions 2 and 4 weeks later. The average of the readings was used for hypertension classification. Hypertension (> 140/90mmHg) was diagnosed according to the Fifth Report of the Joint National Committee (JNCV) of the USA [2]. Cardiac output was assessedby two-dimensional echo-Doppler technique utilizing an Aloka SSD-870 echocardiographic machine (NihonKohden Corp., Tokyo, Japan) in 200 control and all diabetic subjects. Statistical analyseswere carried out using SAS (Statistical Analysing System,SAS Inc., Cary, NC, USA) version 6.06. Data were expressed as mean f S.D. Comparison among groups was undertaken by analysis of variance (ANOVA). Where only two groups were compared, Chisquare test or unpaired t-test was used. A P value < 0.05 was regarded as significant. 3. Results

Details of the study population are outlined in Table 1. The average incidence of borderline hypertension with increased sympathetic activity as noted in diabetic patients, after adjustment for age and sex, was 39% (male 38.4%, female 40.2%), whereas the average incidence of hypertension in non-diabetic subjects was 15.5% (P < 0.001). Analysing the diabetic patients with hypertension

P. Chan et al. /International

Journal of Cardiology

SO (1995)

69-74

71

Table I Baseline demographic, biochemical and hemodynamic data of the control and diabetic patients with normotension Parameters

Male

Female

Control (n = 1315) Age (years) 57.4 + 5.7 Weight (kg) 65.7 * 9.6 0.9 + 0.1 co1 BMI 24.3 i 3.1 Glucose (mg/dl) 98.4 zt 25.9 Insulin (fiU/rnl) 7.7 zt 4.8 Triglyceride (mg/dl) 118.7 zt 72.6 Cholesterol (mg/dl) 200.0 zt 42.0 Pulse (beats/mm) 69.8 zt 9.0 SBP (mmHg) 124.4 f 17.7 79.4 l 10.7 DBP (mmHg) CI (Ymin/mz) (n = 200) 2.6 f 0.1

Normotension (n = 67)

Control (n = 1420)

Normotension (n = 75)

58.9 zt 70.0 f 0.9 l 25.7 f 209.7 f 18.8 l 170.2 f 209.7 f 76.1 f 129.4 f 82.4 f 2.6 f

56.4 f 5.6 58.5 f 8.8 0.81 ct 0.1 24.9 f 3.6 97.7 zt 12.5 8.9 f 5.8 105.6 f 66.3 207.5 f 40.0 68.9 EIZ8.0 122.2 f 18.6 76.2 f 10.3 2.5 f 0.1

57.9 f 61.0 zt 0.9 f 26.0 + 207.8 zt 14.4 i 179.7 l 225.6 A 74.0 zt 131.2 zt 79.4 l 2.4 f

4.7 12.12

0.1 3.8*** 71.8*** 7.1*** 126.4*** 80.0 lO.O*** 15.5* 10.7 0.2

5.7 lO.l** 0.1*** 3.8* 62.6*** 6.4* 119.5**** 41.8*** 7.6* 23.9*** 11.4 0.2

Values are given as mean & SD. COI, central obesity index (waist/hip ratio); BMI, body mass index (kp/m$ SBP, systolic blood pressure; Normotension, diabetic patient with normotension; DBP, diastolic blood pressure; CI, cardiac index. * P < 0.01; ** P < 0.05; *** P < 0.001.

showsthat they were overweight (mean body mass index 26.4 vs. 24.4 kg/m2; P < 0.001). The diabetic patients also had dyslipidaemia which reflected increased levels of triglyceride, cholesterol and a significantly increased level of

apolipoprotein B (Table 2). Hyperinsulinaemia was also noted. The haemodynamic measurements show that the diabetic patients had significantly higher heart rates (mean 78.8 vs. 69.3 beats/mm; P < 0.001)

Table 2 Baseline demographic, biochemical and hemodynamic data between diabetic patients with notmotension and hypertension Parameters

Male

Female

Normotension (n = 67)

Hypertension (n = 25)

Nonnotension (n = 75)

Hypertension (n = 30)

Age (years) Weight (kg) co1 BMI Glucose (mg/dl) Insulin (~&/ml) Triglyceride (mg/dl) Cholesterol (mg/dl) Pulse (beat&tin)

58.9 70.0 0.9 25.7 209.7

58.8 72.2 0.9 26.6 212.8

57.9 61.0 0.9 26.0 207.8

SBP (~8) DBP b@-ht)

129.4 f 15.5 82.4 sz 10.7

58.1 f 4.8 63.6 EIE10.2** 0.9 f 0.1 26.2 + 4.2 205.9 -f 68.9 15.4 l 7.5 181.6 * 120.2 221.7 zt 52.3 78.4 zt 8.2* 142.5 f 16.7*** 89.5 zt 10.8*** 2.4 ct 0.1

CI (Vmin/ms) (n = 200)

f 4.7 12.1 f 0.1 zt 3.8 AZ71.8

l

zt zt f zt f

6.2 10.9** 0.1 4.2 76.9

17.8 f 7.1 170.2 zt 126.4

16.8 l 6.8 174.3 zt 108.3

209.7 f 80.0

212.2 79.2 140.8 92.5 2.6

76.1 zt 10.0 2.6 I 0.1

f f zt zt f

82.5 8.9** 14.5*** 9.5+++ 0.2

* 5.7

f 10.1 l

0.1

zt 3.8 zt 62.6

14.4 f 8.4 179.7 l 119.5 225.6 f 41.8 74.0 A 7.6 131.2 EIZ23.9 79.4 l 11.4 2.4 CIZ0.2

Values are given as mean f S.D. COI, central obesity index (waist/hip ratio); BMI, body mass index (kg/m3; SBP, systolic blood pressure; DBP, diastolic blood pressure; CI, cardiac index. l

P < 0.01; ** P < 0.05;

l

** P < 0.001.

12

P. Chan et al. /International

Journal o/ Cardiology 50 (1995) 69-74

and blood pressure (mean 141/91 vs. 123/V mmHg; P < O.OOl),showing a certain degree of raised sympathetic activity, although we did not measureserum noradrenaline level. As for cardiac output (mean 2.48 vs. 2.53 UminJm2;P > 0.05), the control and study groups showed similar results which were not statistically significant. 4. Discussion Although this study lacks catecholamine data, it still showsa significantly higher heart rate in these diabetic patients. The data show that diabetic patients were relatively obese, with particular increasein upper body fat (android obesity); they also had dyslipidaemia and insulin resistance.The clustering of coronary risks in these patients was obvious. The Tecumseh study has shown that coronary risk factors are strongly interrelated; any one of them could be the key element in the observed association [3-41. This clinical linkage of hypertensive cardiovascular disease,left ventricular hypertrophy and accelerated atherosclerosis with a spectrum of metabolic disturbances including peripheral insulin resistance, hyperinsulinaemia, obesity and frank non-insulin-dependent diabetes mellitus has been increasingly appreciated [ 14,151. However, the biological basis of underlying mechanismsmediating this clinical association remains unclear. Insulin resistance has been postulated as the primary phenomenon, and high insulin in resistant states causes both hypertension and dyslipidaemia [5]. The role of insulin resistancein the development of coronary heart disease has generated considerable interest in recent years. Subjects with coronary heart diseasetend to have a higher insulin response to oral glucose load than subjects without this disease[ 16,171.Hyperinsulinaemia is associated with aggravated profile of cardiovascular risk factors, including obesity, elevated triglyceride levels, low levels of high-density lipoprotein cholesterol and elevated blood pressure

V61. Julius et al. proposed that enhancedsympathetic drive may be the possible mechanism contributing to insulin-resistant dyslipidaemia complex in pa-

tients with hypertension [5]. The relationship between insulin and energy expenditure can be best understood in terms of dietary effects on sympathetic activity. Dietary intake is known to exert a profound influence on the sympathetic nervous system[ 181,as may be briefly summarized: (i) fasting suppresses sympathetic activity [ 19,201; (ii) overfeeding a mixed diet increasessympathetic activity 1211;(iii) a variety of carbohydrates and fats increase sympathetic activity even when total caloric intake is not increased [22-241; and (iv) diets low in protein increase sympathetic activity since the relative proportion of carbohydrate and/or fat is increasedin these diets and since protein per se does not stimulate sympathetic activity [25,26]. Insulin is a major signal that relates dietary intake to sympathetic activity. Insulinmediated glucose metabolism within critical neurons related to the ventromedial portion of the hypothalamus appears to be one important mechanism that couples dietary intake and sympathetic nervous system activity [27]. Intracellular ions measured by nuclear magnetic resonance technique showed that in human erythrocytes, there was a common abnormality of cytosolic sodium, free magnesiumand pH occurring in each of these clinical syndromes [28]. When compared with normotensive subjects, essential hypertension is characterised by higher fasting free cytosolic calcium concentrations and reciprocally lower intracellular free magnesium and pH levels. This phenomenon is also similar to those normotensive obese and/or non-insulin dependent diabetic individuals. A previous epidemiological study in Taipei City, Taiwan, showed that after adjustment for age and sex, the prevalence of hypertension was 16.4% in nondiabetics and 30.6% in diabetics (P c 0.0005) [29]. The 10.2% prevalence of diabetes was also higher in hypertensives compared to 4.9% in normotensives (P < 0.0005) [29]. The present study showssimilar results: the incidence of diabeteswas about 4.8%; the incidence of hypertension in nondiabetic subjects was about 15.5%, whereas the diabetics had a much higher incidence of hypertension of 39.3% (P < O.OOOl),after adjustment for age and sex. Conventionally, vascular risk is intuitively re-

P. Ghan et al. /International

Journal of Car$o/ogy 50 (1995) 69-74

lated to the association of high blood pressure load and of vascular wall damage secondary to chronic hyperglycaemia [30]. In fact, the coronary risk due to these individual pathologic conditions is not simply additive but is potentiated by each other. The higher frequency of the association of sympathetic overactivity, hypertension and noninsulin dependent diabetes suggest that it is not fortuitous. Moreover, diabetic hypertensive subjects also display other vascular risk factors such as dyslipidaemia, rheologic and haemostatic disturbance which increasevascular risk related to diabetes and hypertension. In conclusion, from a therapeutic point of view, blood pressure values (> 140190mmHg) which define hypertension for unselected patients must be reconsidered for diabetic patients. In this subtype of sympathetic overactivity of the diabetic hypertensive patients, calcium antagonists such as verapamil which can reduced heart rate and hyperactivity to stress but has no adverse metabolic effect on lipid and glucose metabolism may be the drug of choice. Angiotensin-converting enzyme inhibitors (ACEI) also do not have untoward metabolic effects Seenwith beta blockers or diuretics. There is no adverse change in lipids and the increase in serum potassium is predictable on pharmacological aspect. ACE1 do not impair glucoseutilisation and probably improve insulin sensitivity in hypertension [31]. This may be of particular importance when hypertension coexists with hyperglycaemia. The best evidence to date that antihypertensive therapy can prevent progession of renal impairment in diabetics also involves ACEI. These agents have recently been demonstrated to decreasethe frequency of renal function deterioration and haemodialysis, even in normotensive diabetic subjects [32]. Acknowledgement The study was supported in part by a grant from the Taipei Institute of Pathology No. TIP 81-10. References [I] National Center for Health Statistics. Health promotion and disease prevention in the United States, 1990. De-

13

partment of Health and Human Services publication (PHS) 95-1513.Hyatsville, MD: Public Health Services, 1993;33. 121Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure.The fifth report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure.Arch Intern Med 1993; 153: 154-183. 131 Julius S, Krause L, Schork N, Meija AD, Jones KA, van de Ven C et al. Hyperkinetic borderline hypertension in Tecumseh, Michigan. J Hypertens 1991;9: 77-84. [41 Julius S, Jamerson K, Meija A, Krause L, Schork N, JonesK. The associationof borderline hypertension with target organ changesand higher coronary risk. Tecumseh blood pressure study. J Am Med Assoc 1990; 264: 354-358. 151Julius S, Jamerson K. Sympathetics, insulin resistance and coronary risk in hypertension: the ‘chicken-and-egg’ question. J Hypertens 1992; 12: 495-502. 161Rowe JW, Young JB, Minaker KL et al. Effect of insulin and glucoseinfusions on sympathetic nervous systemactivity in normal man. Diabetes 1981;30: 219-225. 171 Eich RH, Peters RJ, Cuddy RP, Smulyan H, Lyons RH. The hemodynamics in labile hypertension. Am Heart J 1962; 121: 199-195. F-51Messerli FH, Frohlich ED, Suarez DH et al. Borderline hypertension: relationship between age, hemodynamics and circulating catecholamines. Circulation 1981; 641 760-764. [91 Julius S, Conway J. Haemodynamic studies in patients with borderline blood pressure elevation. Circulation 1968;38: 282-288. 1101Julius S, Pascual AV, London R. Role of parasympathetic inhibition in the hyperkinetic type of borderline hypertension. Circulation 1971;44: 413-418. IllI Barnett AH. Diabetes and hypertension. Br Med Bull 1994,50: 397-407. WI Weidmann P, Boehlen LM, de Courten M. Pathogenesis and treatment of hypertension associated with diabetes mellitus. Am Heart J 1993; 125: 1498-1513. 1131 Yeh CJ, Pan WH, Bai CH et al. Curvilinear relationships between age and haemostatic parameters in Chinese. Thromb Haemost 1994;72: 239-243. ]I41 Reaven GM. Role of insulin resistancein human disease. Banting Lecture, 1988.Diabetes 1988; 37: 1595-1607. 1151Flack JM, Liu K, Savage P. Baseline fasting insulin predicts 2 year blood pressure change in young adults: the CARDIA Study [abstract]. Circulation 1991;83: 724. I161Reaven GM. Role of insulin resistancein human disease in multiple risk factors in cardiovascular disease. In: Gotto AM, Lenfant C, Paoletti R, Soma M, editors. Giovanni Lorenzino Medical Foundation. Dordrecht: Khtwer Academic Publishers, 1992;91-97. [I71 Mitchell BD, Haffner SM, Hazuda HP et al. The relationship between serum insulin levels and I-year changes in lipid, lipoprotein, and blood pressure levels. Am J Epidemiol 1992; 136: 12-22.

74

P. Chan et al. /International

Journal of Cardiology SO (1995) 69-74

[18] Landsberg L, Young JB. The inIluence of diet on the sympathetic nervous system. In: Muller EE, MacLeod RM, Forhman LA, editors. Neuroendocrine perspectives. Amsterdam: Elsevier Science Publishers, 1985; 191-218. [ 191 Young JB, Landsberg L. Suppressionof sympathetic nervous system during fasting. Science 1977; 196: 1473- 1475. [20] Young JB, Rosa RM, Landsberg L. Dissociation of sympathetic nervous system and adrenal medullary responses.Am J Physiol 1984;247: E35-E40. 1211 Young JB, Savilie E, Rothwelf NJ, Stock MJ, Landsberg L. Effect of diet and cold exposure on norepinephrine turnover in brown adipose tissue in the rat. J Clin Invest 1982;69: 1061-1071. 1221 Young JB, Landsberg L. Stimulation of the sympathetic nervous systemduring sucrosefeeding. Nature 1977;269: 615-617. [23] Schwartz JH, Young JB, Landsberg L. Effect of dietary fat on sympathetic nervous system activity in the rat. J Clin Invest 1983;72: 361-370. 1241 Walgren MC, Young JB, Landsberg L. Effect of different carbohydrates in sympathetic activity in heart and interscapular brown adipose tissue (IBAT) of the rat. Sot Neurosci Abstr 1985; II (part 2): 764. [ZS] Young JB, Kaufman LN, Saville ME, Landsberg L. In-

creasedsympathetic nervous system activity in rats fed a low protein diet. Am J Physiol 1985;248: R627-R637. [26] Kaufman LN, Young JB, Landsberg L. Effect of protein on sympathetic nervous system activity in the rat: evidence for nutrient-speciIic responses.J Clin Invest 1986; 77: 551-558. [27] Landsberg L, Young JB. Insulin-mediated glucose metabolism in the relationship between dietary intake and sympathetic nervous system activity. Int J Obes 1985;9 (suppl 2): 63-68. [28] Resnick LM. Cellular ions in hypertension, insulin resistance, obesity, and diabetes: a unifying theme. J Am Sot Nephrol 1992;3: S78-S85. [29] Hamet P. Hypertension and diabetes. Chn Exp Hypertens 1993; 1.5:1327- 1342. 1301 Marre M, Berrut G, Bouhanick. Hypertension and diabetes mellitus. Biomed Pharmacother 1993; 47: 61-66. [31] Pollare T, Lithell H, Beme C. A comparison of the effects of hydrochlorothiaxide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl J Med 1989;321: 868-873. 1321 Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensinconverting-enxyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993; 329: 1456-1462.