Effects of coexisting hypertension and type II diabetes mellitus on arterial stiffness

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1 (2004) 18, & 2004 Nature Publishing Group All rights reserved /04 $ ORIGINAL ARTICLE Effects of coexisting hypertension and type II diabetes mellitus on arterial stiffness MA Tedesco, F Natale, G Di Salvo, S Caputo, M Capasso and R Calabró Department of Cardio-Thoracic and Respiratory Sciences, Second University of Naples, Monaldi Hospital, Naples, Italy Hypertension (HT) is frequently associated with diabetes mellitus (DM) and its prevalence doubles in diabetics compared to the general population. This high prevalence is associated with increased stiffness of large arteries, which often precedes macrovascular events. The aim of our study was to evaluate the influence of HT and type II DM on aortic stiffness in patients with one disease or the other compared to those with both HT and type II DM. We studied 220 patients, 50 with type II DM (Group A), 50 with HT (Group B), 85 with both diseases (Group C), and 35 healthy subjects (HS). Regional arterial stiffness was assessed by automatic measurement of the carotid femoral pulse wave velocity (PWV). For each patient, we evaluated: age, sex, body mass index, smoking habit, heart rate, SBP/DBP, pulse pressure (PP), mean BP, fasting glucose, lipid profile, uric acid, and fibrinogen. Group C had significantly more women and non smokers and the highest PP (61714 mmhg). Of biochemical parameters, only fibrinogen was higher in Group A and in Group C (Po0.01 and Po0.001, respectively). Group C had a significantly higher PWV than the other four groups (Po0.0001). Stepwise forward regression analysis showed that fasting glucose was the first independent determinant of PWV (Po0.0001). In conclusion, this study shows that patients with DM and HT have higher arterial stiffness compared to HS and those with one disease or the other. Fasting glucose is the major independent determinant of PWV, which may be used as a relevant tool to assess the influence of cardiovascular risk factors on arterial stiffness in high-risk patients. (2004) 18, doi: /sj.jhh Published online 26 February 2004 Keywords: type II diabetes mellitus; arterial stiffness; pulse wave velocity; pulse pressure Introduction Hypertension (HT) and diabetes mellitus (DM) are on the rise in industrialised nations because populations are ageing, and both increase with age. Frequently, HT is associated with DM and its prevalence doubles in diabetics compared to the general population. 1,2 Many type II diabetics develop HT. This high prevalence is associated with increased stiffness of large arteries, which often precedes macrovascular events. 3,4 The arterial system propagates pressure and flow waves at a certain velocity largely determined by the elastic properties of the arterial wall. 5 Aortic stiffness can be assessed noninvasively in large populations by measuring carotid femoral pulse wave velocity (PWV), a simple and reproducible method. 6,7 Several studies have shown significant interactions between PWV Correspondence: Dr MA Tedesco, Salita Due Porte 14, Naples 80136, Italy. tedesco@pandoranapoli.it Received 06 August 2003; revised 22 December 2003; accepted 06 January 2004; published online 26 February 2004 and the major cardiovascular risk factors, such as age, gender, HT, DM, smoking, and a close correlation with atherosclerosis In the presence of atherosclerotic lesions, a high carotid femoral PWV was found even after adjustments on confounding factors. 10 Little is known about the effect of both high blood pressure (BP) and DM on aortic stiffness The aim of our study was to evaluate the influence of BP and type II DM on aortic stiffness in patients with one disease or the other compared to those with both HT and type II DM. Methods Study population This investigation studied aortic stiffness in diabetic, hypertensive, and diabetic and hypertensive patients, who attended the outpatient HT clinic at the Second University of Naples between January and October We selected 185 patients, 50 with type II DM (Group A, mean age 5577 years, 34 men), 50 with HT (Group B, mean age years,

2 men) and 85 with type II DM and HT (Group C, mean age 5578 years, 33 men), for whom arterial stiffness measurements by PWV were available. A control group included 35 healthy subjects (HS, mean age 5277 years, 21 men). Participants had been diagnosed with DM and HT for at least 1 year (duration of both diseases: ). The diagnosis of HT was considered when SBP was 4140 mmhg and/or DBP 490 mmhg and when antihypertensive therapy was present. BP was measured by a mercury sphygmomanometer with an appropriate size rubber cuff. Readings were based on Korotkoff first and fifth phase sounds. Three consecutive BP readings were obtained with the subject in supine position after a rest of at least 15 min. The average of the last two readings was used for the analyses, recorded to the nearest 2 mmhg on the scale. Measurements were performed early in the morning and carried out by a trained investigator. Type II DM was defined as a fasting blood glucose level 4126 mg/dl (7.0 mmol/l), confirmed on a subsequent day, according to the report of the Expert Committee on the diagnosis and classification of DM, 14 or use of hypoglycaemic agents. None had any evidence or history of atherosclerotic disease, myocardial infarction, or stroke. Patients with cardiovascular conditions who can produce altered BP waveforms, including arrhythmias, valvular heart disease, or congestive heart failure, were excluded. Additional exclusions were being overweight, defined as a body mass index (BMI) 435 kg/m 2 and smoking more than 20 cigarettes per day. In the 4 h before the instrumental procedures, subjects were prohibited from eating, smoking, drinking coffee, or doing any heavy physical activity. All patients followed a diet with normal salt intake (3 g/day). Among hypertensive patients, 61 subjects used antihypertensive drug therapy: ACE inhibitors (n ¼ 30), calcium antagonists (n ¼ 21), beta-blockers (n ¼ 5), diuretics (n ¼ 5); among diabetic patients, 80 were receiving hypoglycaemic agents: sulphamides (n ¼ 30), and/or biguanids (n ¼ 50). Pharmacological treatment was stopped 4 days before inclusion. Moreover, for each patient we evaluated clinical parameters such as age, sex, BMI, smoking habit, heart rate, pulse pressure (PP, defined as systolic BP minus diastolic BP), and mean BP (MBP, calculated as MBP ¼ DBP þ PP/3). We also determined lipid profile, uric acid, and fibrinogen in the serum. Venous blood samples were obtained after an overnight fast. Each subject provided informed consent for the study. PMV measurement Regional arterial stiffness was assessed by carotid femoral PWV. The acquisition frequency of pressure waveforms was 500 Hz obtained by using two pressure transducers with a large-frequency bandwidth (TY-306; Fukuda Denshi Co., Tokyo, Japan) connected to an automatic processor (Complior s ; Colson AS, Paris, France). Assessment of arterial stiffness by PWV measurement is a standardised, repeatable and widely used method. 6 It is based on a simple technique, which consists of recording pressure waveforms at two different arterial sites: at the base of the neck for the common carotid artery and over the right femoral artery. The pulse transit time between the two recording sites is related to the distance between the two points of measurement. The on-line computerised measurements were analysed using an algorithm based on the time-shifted and repeated linear correlation calculation between the initial rise in the pressure waveforms. All measurements were performed, after 15 min of supine rest, by the same observer, who was blind to the BP of the subject. Since the biophysical properties of the aorta can vary on a short-term basis, possibly as a result of sympathetic activity, a minimum of 10 and a maximum of 22 measurements were performed and used for the calculation of the mean velocity. The inter-intraobserver reproducibility coefficients were 40.90, calculated in a sample of 35 normal subjects. Statistical analysis Statistical analysis was carried out by Stat View software (SAS Institute, Cary, NC, USA). Comparison among groups was performed using ANOVA plus Bonferroni s t-test for unpaired data. Bonferroni s correction was used to assess differences (P values p0.008 indicated significance). Comparisons of categorical data were made using Fisher s exact test. Stepwise forward regression analysis was performed to assess which factors independently influence PWV and was used to determine which variable was selected first. Variables selected for inclusion in the model were those significant at univariate analysis. Significance was defined as Po0.05. Results Table 1 shows the anthropometric characteristics and the haemodynamic parameters of the groups. There were no significant differences in age, BMI, and heart rate among the four groups. The hypertensive diabetic group had significantly more women and nonsmokers and the highest PP (61714 mmhg). Of the biochemical parameters, only fibrinogen was significantly higher in Group A and in Group C (Po0.01 and Po0.001, respectively). The highest PWV were observed in patients with hypertension and type II DM (Group C), showing a significant difference compared to the other groups (Po0.0001). Stepwise forward regression analysis (Table 2) showed that fasting glucose followed by MBP were independent predictors of

3 Table 1 Clinical characteristics of the four groups 471 Group A Group B Group C HS (n ¼ 50) (n ¼ 50) (n ¼ 85) (n ¼ 35) Age (years) Men (%) *^ 60 Body mass index (kg/m 2 ) Smokers (%) 42** Fasting glucose (mmol/l) *** *** SBP (mmhg) w w DBP (mmhg) 7778 w w Pulse pressure (mmhg) y y MBP (mmhg) 9478 w w Heart rate (b.p.m) Total cholesterol (mmol/l) HDL-cholesterol (mmol/l) Triglycerides (mmol/l) Uric acid (mmol/l) Fibrinogen (mg/dl) Pulse wave velocity (m/s) z z ww Values are means7s.d. or number (%). Group A: diabetic patients; Group B: hypertensive patients; Group C: diabetic and hypertensive patients; HS: healthy subjects. *Po0.001 vs Group A, ^Po0.05 vs Group B and HS, **Po0.01 vs Group C, ***Po vs Group A and C, w Po vs Group B and C, y Po Group A vs Group C, HS vs Group B and C, 1Po0.01 vs Group B, 11Po vs B, ww Po vs A, B and HS, z Po vs HS. Table 2 Independent predictors for pulse wave velocity by stepwise forward regression analysis in the study population PWV (Po0.0001). We introduced MBP into the model, rather than SBP/DBP and PP, because MBP is not directly dependent on arterial stiffness. Discussion b-coefficient Standard error (b) Smokers Fasting glucose o Sex MBP o Fibrinogen Multiple R ¼ 0.47; R 2 ¼ The main result of this study is that arterial stiffness, measured through PWV, was higher in patients with both DM and HT. The analysis showed the greater influence of DM on increasing arterial stiffness and that fasting glucose is the first independent determinant of PWV. Diabetics had a slightly higher PWV with a lower MBP than hypertensives and diabetic/hypertensive patients had a greatest PWV with no significant difference in MBP compared to hypertensives. The observed differences in PWV among groups cannot be attributed to other variables (such as age, BMI, and heart rate) since they were similar in all of them. However, the highly significant correlation between PWV and another risk factor, fasting glucose, suggests an t P underlying diffuse atherosclerosis involving large arteries. Morbidity and mortality in diabetes are caused mainly by vascular complications in the microcirculation and large vessels, and consist of accelerated atherosclerosis. 3,15,16 Changes in arterial stiffness have been observed even at an early stage of disease and in young nondiabetic adults with a family history of type II DM. The prevention of micro- and macroangiopathy requires tight blood glucose control. 17 The results of several studies, analysing the effect of DM on the arterial wall, are heterogeneous despite a general tendency toward an increase of the arterial stiffness in diabetics. 18 The mechanism of increased arterial stiffness relates to changes in elastin and collagen within the walls; the elastin fibres become fractured and collagen deposition is increased. Moreover, high glucose levels promote the formation of advanced glycation end-products, which has been associated with changes in the vessel walls. On the other hand, the role of hyperglycaemia in the physiopathology of macroangiopathy remains controversial and the prevention of macrovascular events seems to involve the treatment of cardiovascular risk factors associated with DM, essentially HT. 19 There is strong evidence that in essential HT, the main change in vasculature resistance is a change in structure; the stiffness of arteries is strongly influenced by transmural distending pressure and hence by MBP. The prevalence of HT is at least twice as high in the diabetic population as in the background population. In type II DM, arterial HT plays an important role in the initiation and the progression of diabetic micro macroangiopathy, and both are the most important risk factors for cardiovascular

4 472 disease. 11 By increasing arterial stiffness, HT may accelerate progression of complications in type II DM. It is well established that arterial structural and functional abnormalities are observed in hypertensives even at an early stage of disease These alterations modify physiological and mechanical properties of the arterial wall, which may become clinically evident by increasing PP, making it easier to establish the progression of atherosclerosis. In our study, the highest value of PP in diabetic hypertensives may reflect already diseased arterial walls, with several adverse cardiac implications of potential prognostic value. 23,24 PP arises from the interaction of cardiac ejection (stroke volume) and viscoelastic properties of large arteries. An increased stiffness of the aorta and large arteries leads to an increase in PP through a reduction in arterial compliance and a premature return of reflected waves in late systole, increasing the load on the ventricle and increasing myocardial oxygen demand. 25 These abnormalities can be attributed not only to the stretching effects of elevated BP but also to intrinsic alterations of the arterial wall, which could represent either adaptive structural and functional changes secondary to the chronic increase in BP, or primary abnormalities of the vessel wall. Local hormonal factors may play a role in the modification of the arterial wall, mainly by modifying cell growth or synthesis of the extracellular matrix. 26 Among these factors, angiotensin II may be of particular importance, since it induces hypertrophy of vascular smooth muscle cells in culture and increases collagen production by fibroblasts, mediated by the effects of this peptide on the AT1 receptors. 27,28 These outcomes may be useful as additional factors in risk assessment for future therapeutic decision-making. Change in BP is a poor indicator of changing resistance in vessel structure. Although the effect on BP may be the same, trials have shown that antihypertensive treatments have different effects on the arterial wall A therapeutic strategy is not only able to reduce glycaemia, BP, and concomitant risk factors but also to reduce aortic stiffness, and may be an effective way to lower cardiovascular morbidity and mortality in hypertensive diabetics. Moreover, among risk factors, it is useful to underscore the importance of fibrinogen, a recognised marker of cardiovascular risk, which we observed to be significantly increased in diabetic patients with or without HT. This confirmed the well-known association between blood glucose and fibrinogen. 32 In conclusion, this study shows that patients with diabetes and HT have higher arterial stiffness compared to those with one disease or the other. Fasting glucose is the first independent determinant of PWV that may be used as a relevant tool to assess the influence of cardiovascular risk factors on arterial stiffness in high-risk patients. References 1 Barrett-Connor E, Criqui MH, Klauber MR, Holdbrook M. Diabetes and hypertension in a community of older adults. Am J Epidemiol 1981; 113: Teuscher A, Egger M, Herman JB. Blood pressure in clinical diabetic patients and a control population. Arch Intern Med 1989; 149: Lehmann ED, Gosling RG, Sönksen PH. Arterial wall compliance in diabetes. Diabet Med 1992; 9: Benetos A, Laurent S, Asmar R, Lacolley P. Large artery stiffness in hypertension. J Hypertens 1997; 15 (Suppl 2): S89 S97. 5 Asmar R et al. Noninvasive evaluation of arterial abnormalities in hypertensive patients. J Hypertens 1997; 15 (Suppl 2): Asmar R et al. Assessment of arterial distensibility by automatic pulse wave velocity measurement. Hypertension 1995; 26: Asmar R et al. Pulse wave velocity as endpoint in large-scale intervention trial. The Complior study. J Hypertens 2001; 19: Amar J et al. Arterial stiffness and cardiovascular risk factors in a population-based study. J Hypertens 2001; 19: Laurent S et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 2001; 37: Van Popele NM et al. Association between arterial stiffness and atherosclerosis: The Rotterdam study. Stroke 2001; 32: Cockcroft JR, Webb DJ, Wilkinson IB. Arterial stiffness, hypertension and diabetes mellitus. J Hum Hypertens 2000; 14: Aoun S, Blacher J, Safar ME, Mourad JJ. Diabetes mellitus and renal failure: effects on large artery stiffness. J Hum Hypertens 2001; 15: Parving HH. Diabetic hypertensive patients. Is this a group need of particular care and attention? Diabetes Care 1999; 22 (Suppl 2): B76 B American Diabetes Association. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003; 26 (Suppl 1): S5 S Woolam GL, Schnur PL, Vallbona C, Hoff HE. The pulse wave velocity as an early indicator of atherosclerosis in diabetic subjects. Circulation 1962; 25: Wahlqvist ML, Relf IR, Myers KA, Lo CS. Diabetes and macrovascular disease: risk factors for atherogenesis and noninvasive investigation of arterial disease. Hum Nutr Clin Nutr 1984; 38: DCCT Research Group. The effect of intensive diabetes treatment on the development and progression of longterm complications in insulin-dependent diabetes mellitus: the diabetes control and complications trials. N Engl J Med 1993; 329: Kool MJ et al. Vessel wall properties of large arteries in uncomplicated IDDM. Diabetes Care 1995; 18: UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:

5 20 Isnard R et al. Pulsatile diameter and elastic modulus of the aortic arch in essential hypertension: a noninvasive study. J Am Coll Cardiol 1989; 13: O Rourke M. Mechanical principles in arterial disease. Hypertension 1995; 26: Asmar R et al. Aortic distensibility in normotensive untreated and treated hypertensive patients. Blood Press 1995; 4: Franklin SS et al. Haemodynamic patterns of agerelated changes in blood pressure: the Framingham study. Circulation 1997; 96: Safar ME. Pulse pressure in essential hypertension: clinical and therapeutic implications. J Hypertens 1989; 7: Nichols WW, O Rourke M. Theoretical, experimental and clinical principles. In: Arnold E (ed). McDonald s Blood Flow in Arteries, 3rd edn. Lea and Febier: London, 1990, pp , , , Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 2000; 52: Williams B. Angiotensin II and the pathophysiology of cardiovascular remodeling. Am J Cardiol 2001; 87 (Suppl): 10C 17C. 28 Bunkenburg B, van Amelsvoort T, Rogg H, Wood JM. Receptor-mediated effects of angiotensin II on growth of vascular smooth muscle cells from spontaneously hypertensive rats. Hypertension 1992; 20: Asmar RG et al. Comparison of effects of felodipine versus hydrochlorothiazide on arterial diameter and pulse wave velocity in essential hypertension. Am J Cardiol 1993; 72: Benetos A et al. Arterial stiffness, hydrochlorothiazide and converting enzyme inhibition in essential hypertension. J Hum Hypertens 1996; 10: Mahmud A, Feely J. Effect of angiotensin II receptor blockade on arterial stiffness: beyond blood pressure reduction. Am J Hypertension 2002; 15: Barazzoni R et al. Insulin acutely increases fibrinogen production in individuals with type 2 diabetes but not in individuals without diabetes. Diabetes 2003; 52:

Nomogram of the Relation of Brachial-Ankle Pulse Wave Velocity with Blood Pressure

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