Serum Cholesterol Affects Blood Pressure Regulation

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Journal of Human Hypertension (2002) 16, 337–343  2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh ORIGINAL ARTICLE Serum cholesterol affects blood pressure regulation

LA Ferrara, L Guida, R Iannuzzi, A Celentano and F Lionello Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy

A close relationship between abnormalities of the lipid ferent for serum cholesterol and triglycerides. BP at rest metabolism and arterial hypertension has been and during 24-h monitoring was similar in the three observed in several epidemiological studies. The aim of groups, whilst a significant difference was detected dur- the present study was to investigate whether serum ing sympathetic stimulation by handgrip, with systolic cholesterol might affect blood pressure (BP) levels at and diastolic BP increasing by 16/12, 28/19 and 30/23 rest, during ambulatory monitoring or during sympath- mm Hg (P Ͻ 0.01) in lower, medium and higher tertiles, etic stimulation—independently of other variables such respectively. Intima-media layer of the carotid arteries as body weight or serum insulin—thus influencing the was also significantly thickened in the groups with outcome of hypertensive complications. Seventy-three higher cholesterol levels (0.54 ± 0.07, 0.67 ± 0.14, patients with sustained newly-discovered and never- 0.68 ± 0.15, P Ͻ 0.05). These data support the con- treated hypertension were divided into tertiles accord- clusion that even in patients with recently discovered ing to their serum cholesterol levels and their resting hypertension, cholesterol levels may influence the BP BP, 24-h BP and BP during isometric exercise response to adrenergic stimulation as well as the out- (handgrip) were compared. Cardiac mass and carotid come of target organ disease. wall thickness were measured by echographic tech- Journal of Human Hypertension (2002) 16, 337–343. DOI: nique. The results were that tertiles were similar for 10.1038/sj/jhh/1001388 body weight, blood glucose and serum insulin, but dif-

Keywords: serum cholesterol; blood pressure; handgrip; endothelium function

Introduction In order to contribute to this interesting topic, the present investigation aimed at evaluating possible Epidemiological investigations have found that differences in BP levels at rest, during 24-h monitor- hypertensive patients frequently have a concomitant 1,2 ing, and during sympathetic stimulation induced by increase in serum cholesterol levels. Whether this handgrip isometric exercise, in hypertensive is only a pure statistical association or it also implies patients according to their fasting serum choles- a pathophysiological link is still under discussion. terol levels. Endothelium, in fact, plays a role in the regulation of systemic blood pressure (BP) and local vascular tone, as suggested by some authors in the last few Patients and methods years.3 The same factors able to affect the endo- Seventy-three patients with recently discovered and thelium might, in turn, influence BP levels. Thus, never-treated arterial hypertension (high BP levels lipoproteins, which strongly contribute to athero- recently detected with a previous finding of normal genesis, might play a relevant role in the pathophy- values within 1 year) were invited to enter the study. siology of arterial hypertension:4 this hypothesis is Exclusion criteria were: (a) white-coat hyperten- further supported by the observation that hypertension; (b) biochemical or instrumental evidence of sion and atherosclerosis share structural and func- secondary hypertension; (c) total cholesterol tional changes. High cholesterol has been shown to Ͼ7.76 mmol/L and/or triglycerides Ͼ3.39 mmol/L impair endothelium-dependent dilation,5 which (without nutritional or pharmacological treatment); seems to be restored by oral administration of L- (d) fasting blood glucose Ͼ6.94 mmol/L (without arginine in hypercholesterolaemic patients.6 nutritional or pharmacological treatment); (e) evidence of cardiovascular disease (myocardial infarc- tion, angina, stroke or transient ischaemic attacks in Correspondence: LA Ferrara, MD, Department of Clinical and the past 6 months or evidence of cardiac valvular Experimental Medicine, Federico II University, Via S. Pansini, 5, 80131, Naples, Italy. E-mail: ferraraȰunina.it disease); (f) evidence of liver cirrhosis or renal fail- Received 30 October 2001; revised and accepted 19 December ure; and (g) pregnancy or lactation. 2001 After a 1-month run-in during which their BP was Serum cholesterol affects blood pressure regulation LA Ferrara et al 338 measured at rest three times at 2-week intervals, ducer and recorded on videotapes. Strip-chart trac- patients were asked to give their informed consent ings of the patients were obtained at 50 mm/sec to participate. Thereafter they underwent the follow- velocity; these were examined by two experienced ing measurements: investigators blind to the knowledge of the status of (1) Height and weight, using a platform beam- patients, using a graphic tablet and a pointer device scale (Seca 760); body mass index (BMI), calculated interfaced with a PC and a customised data-acqui- as weight-to-squared height ratio (w/h2). sition software. In our laboratory, the interobserver (2) Resting BP, using an automatic sphygmoman- variability for measurements of wall thickness, ometer (Sentron, Bard Biomedical, Lombard, IL, internal dimensions and left ventricular mass was USA).7 Two BP readings were recorded with very small with an interclass correlation coefficient patients in the sitting position for at least 5 min, of 0.90. End-diastolic (EDD) and end-systolic (ESD) between 9.00 and 11.00 in the morning; the average left ventricular internal diameters, posterior wall of the two readings was considered as the measure- (PWT) and septal thicknesses (SWT) were measured ment for that visit. Patients were also asked to com- according to the recommendations of the American plete a questionnaire regarding smoking habits. Society of Echocardiography.10 A second set of (3) Twenty-four hour ambulatory BP monitoring measurements was also taken according to the Penn (ABPM), by Spacelabs Inc 90207 (Redmond, WA, convention criteria to calculate left ventricular mass USA), during a normal working day. The monitor (LVM).11 To take into account body size, LVM was was fitted on in the morning, between 10.00 and normalised for body height to the power of 2.7 12.00 am. Subjects were asked to perform their nor- (LVMi = g/m2.7), an indexation that has been shown mal daily activities and to consume their habitual to also detect hypertrophy in obese individuals.12 diet. The monitor was programmed to record BP and Relative wall thickness (RWT), an index of LV geo- heart rate (HR) at 15-min intervals during the sub- metric pattern, was measured at end-diastole, as 2 * jects’ waking hours and at 20-min intervals during PWT/EDD. The aortic root (AR) was measured their usual sleeping hours. Subjects were instructed according to the recommendations of the American to keep their arms still during recordings. For the Society of Echocardiography. Left atrium (LA) size analysis of the data, the 24-h measurements were was measured from the trailing edge to the leading divided into waking (7.00 am to 10.45 pm) and edge, by excluding the posterior wall of the aortic sleeping (11.00 pm to 6.40 am) periods. The 24-h root. LV end diastolic (EDV) and systolic (ESV) vol- record was acceptable if more than 80% of the umes were calculated using the Teichholz correc- scheduled readings were available. Patients also tion of the cube formula.13 LV chamber and stroke filled in a 24-h diary to report daily activities and volumes (SV) determined using this approach have rest, including the sleeping period. been shown to correlate well with invasive and (4) BP was also measured during isometric exer- Doppler echocardiographic volume measurements cise. Patients refrained from smoking and drinking in a variety of populations with symmetric LV wall beverages containing caffeine for at least 12 h before motion.14 Cardiac output (CO) and ejection fraction the test. The handgrip was performed, after a 15-min (EF) were also calculated. bed rest, by squeezing a dynamometer for 3 min at (7) Carotid ultrasound imaging was performed 30% of previously evaluated maximal stress. BP and with a 2000 II SA Biosound ultrasound system, (Bio HR were measured twice before the test, three times Dynamics, Indianapolis, IN, USA) according to the at 1-min intervals during the test and twice, after 2 methodology already described.15,16 Ultrasono- and 5 min, in the recovery phase. The average of BP graphic images were considered acceptable only if and HR measurements at baseline, during the stress, they met the criteria for a high quality examination, and in the recovery phase were calculated for the that is: (a) presence of the adventitia-media interface statistical analysis of the tests.8 and intima-lumen interface in at least two arterial (5) Laboratory assessments of haematology segments; (b) visualisation of anterior, posterior, lat- (haematocrit = Ht) and biochemistry (fasting blood eral and medial wall of the common carotid artery, glucose (FBG), serum insulin, total proteins, total the bifurcation and at least 2 cm of the internal serum cholesterol (Chol), triglycerides (Tg), and carotid artery. The whole scanning procedure was cholesterol content in high-density lipoproteins recorded on a videotape; a hard copy of the distal (HDL chol)). Blood samples were drawn at 8.30 am, portion of the common carotid artery, just below the after an overnight fast. Cholesterol content in the bulb, was thereafter produced. Pictures were low-density lipoproteins (LDL chol) was calculated scanned (Epson G 2000) and displayed on a com- by the Friedewald formula,9 as follows: puter screen (Macintosh II) and then analysed by a software (Image 1.31) that allows quantitative evalu- LDL chol = total chol − (HDL chol + 1/5 Tg) ation of the terminal centimer of the vessel intima- (6) Two-dimensionally-targeted M-mode echocar- media area. Measurement of mean intima-media diograms were performed by an expert sonographer, thickness (IMT) of the common carotid arteries was using a commercially available echocardiograph derived from the area-to-1 cm length ratio. Lumen (AU3 Partner ESAOTE Biomedica, Florence, Italy) diameter was also measured at the same level. connected to a 2.5 to 3.5 MHz annular-array trans- Thickness of the common carotid artery was meas-

Journal of Human Hypertension Serum cholesterol affects blood pressure regulation LA Ferrara et al 339 Table 1 Age, sex, body mass index, smoking habits, blood pressure (BP), heart rate and metabolic parameters in 73 patients with hypertension recently discovered and never treated, divided according to tertiles of serum cholesterol levels

1st 2nd 3rd P (Ͻ5.172 mmol/L) (5.172–5.922 mmol/L) (Ͼ5.922 mmol/L)

Age (yrs) 41.0 ± 11 42.9 ± 9 44.8 ± 5NS Sex (M/F) 16/8 20/6 16/7 NS Body mass index (kg/m2) 27.7 ± 3.4 26.4 ± 3.6 26.4 ± 2.6 NS Smoking (%) 50 54 53 NS Systolic BP (at rest) (mm Hg) 153.4 ± 19.1 150.1 ± 11.3 148.8 ± 11.6 NS Diastolic BP (at rest) (mm Hg) 99.6 ± 7.2 99.1 ± 5.5 98.3 ± 6.3 NS Heart rate (at rest) (bpm) 77.9 ± 14.0 72.3 ± 10.9 73.8 ± 12.1 NS 24-h systolic BP (mm Hg) 139.4 ± 14.5 139.7 ± 11.9 138.5 ± 15.5 NS 24-h diastolic BP (mm Hg) 90.4 ± 11.3 91.8 ± 8.1 91.8 ± 9.7 NS 24-h heart rate (bpm) 75.5 ± 6.6 75.5 ± 8.6 75.8 ± 9.5 NS Total cholesterol (mmol/L) 4.45 ± 0.49 5.50 ± 0.23* 6.65 ± 0.55*† 0.001 Total triglyceride (mmol/L) 1.13 ± 0.42 1.39 ± 0.53 1.70 ± 0.81* 0.01 HDL-cholesterol (mmol/L) 1.07 ± 0.24 1.16 ± 0.27 1.29 ± 0.50 NS LDL-cholesterol (mmol/L) 3.23 ± 0.42 4.08 ± 0.25* 5.05 ± 0.50*† 0.001 Fasting blood glucose (mmol/L) 5.17 ± 0.68 5.34 ± 0.58 5.39 ± 0.61 NS Serum insulin (pmol/L) 87.9 ± 59.8 71.4 ± 25.3 68.3 ± 22.8 NS

Significances: * vs 1st tertile; † vs 2nd tertile. ured only at the level of the far wall (the carotid The patients were divided, retrospectively, into ter- wall farthest from the probe) as this segment is more tiles according to their serum cholesterol levels. The constantly visualised with B-mode imaging than the tertiles comprised (a) patients with cholesterol more superficial near wall.15,16 This technique below 5.172 mmol/L, (b) those with cholesterol allows a high reproducibility of the measurements, between 5.172 and 5.922 mmol/L, and (c) patients as already shown in a previous study.17 with serum cholesterol above 5.922 mmol/L. As shown in Table 1 these groups were similar for Protocol age, sex, BMI and smoking habit; also BP levels, both at rest and during 24-h monitoring, were similar in Patients arrived at the Outpatient Hypertension the tertiles. Clinic, after an overnight fast, at 8.00 am. In the first BP response to sympathetic stimulation by a day they underwent the clinical procedures accord- 3 min handgrip showed the systolic and diastolic BP ing to the following schedule: (a) measurement of increase during the test to be significantly more pro- BP at rest; (b) venous sampling for biochemical nounced in hypertensive patients with high choles- analysis; (c) two-dimensionally targeted M-mode terol levels than in the first subgroup (systolic BP echocardiographic assessment; (d) carotid ultra- (SBP) increase 16 ± 7, 28 ± 12, 30 ± 13 mm Hg, sound imaging; (e) measurement of BP during a 3- P Ͻ 0.01; diastolic BP (DBP) increase 12 ± 4, 19 ± 10, min isometric exercise; and (f) start of 24-h BP moni- 23 ± 10 mm Hg, P Ͻ 0.01, mean BP (MBP) increase toring. 14 ± 4, 22 ± 10, 26 ± 10 mm Hg, P Ͻ 0.01) (Figure 1), The day after patients returned to the outpatient without difference in heart rate (HR) (7.8 ± 6, 9.4 ± 8, clinic to undress the ABP monitor. Protocol of the ± study was approved by the local Institutional Ethi- 9.3 6 beats per min). cal Committee. With regard to biochemistry, all lipid parameters but not HDL-cholesterol progressively increased from the first to the last subgroup whilst no differ- Statistical analysis ence was detected in glucose metabolism (Table 1). Data were stored and analysed by SPSS statistical Echocardiographic parameters of cardiac structure package. Data are expressed as mean ± standard and systolic function were similar in the three sub- deviation (M ± s.d.) in the text and in the tables, and groups (Table 2), whereas a significant thickening of as M ± SE in the figures. Normally distributed the carotid wall was detected in patients with higher variables were compared by one-way analysis of cholesterol levels. Figure 2 shows that mean variance with Tukey’s multiple comparisons, and (0.54 ± 0.07, 0.67 ± 0.14, 0.68 ± 0.15 mm, P Ͻ 0.05) categorical ones by ␹2 test. A P value of 0.05 was and peak (0.64 ± 0.12, 0.75 ± 0.13, 0.76 ± 0.16 mm, considered significant. P Ͻ 0.05) thickness of the intima-media layer are significantly increased in the second and third tertiles without differences in the carotid diameter Results (6.25 ± 1.12, 6.25 ± 0.70, 6.57 ± 0.90 mm). Seventy-three patients with sustained arterial hypertension, age range 17–64 years, entered the study.

Journal of Human Hypertension Serum cholesterol affects blood pressure regulation LA Ferrara et al 340

Figure 1 Systolic, diastolic and mean blood pressure increase during isometric exercise in 73 hypertensive patients divided according to tertiles of serum cholesterol levels (M ± s.e., signiﬁcance 1st vs other tertiles *P Ͻ 0.01).

Table 2 Parameters of cardiac structure and function in 73 patients with hypertension recently discovered and never treated, divided according to tertiles of serum cholesterol levels

1st 2nd 3rd P (Ͻ5.172 mmol/l) (5.172–5.922 mmol/l) (Ͼ5.922 mmol/l)

Septal wall thickness (mm) 10.8 ± 1.6 10.7 ± 1.3 10.8 ± 1.3 NS Posterior wall thickness (mm) 10.1 ± 1.7 9.5 ± 1.3 10.3 ± 1.2 NS Left ventricular mass (i) (g/m2.7) 44.9 ± 8.7 44.7 ± 7.2 48.2 ± 15.4 NS Relative wall thickness 0.42 ± 0.07 0.38 ± 0.06 0.40 ± 0.05 NS Left atrium (mm) 36.7 ± 5.6 36.4 ± 4.1 36.4 ± 3.4 NS Aortic root (mm) 29.8 ± 4.3 29.7 ± 2.5 29.3 ± 4.9 NS Stroke volume (mL) 73.2 ± 13.5 76.5 ± 13.4 83.0 ± 17.9 NS Cardiac output (L/m) 5.5 ± 1.3 5.7 ± 1.3 6.1 ± 1.4 NS Ejection fraction (%) 64.0 ± 9.5 66.8 ± 5.6 69.7 ± 9.3 NS

Discussion different factors such as altered peripheral insulin 23 18,19 sensitivity or genetically-determined abnormali- Large prospective studies have pointed out that ties of the trans-membrane transport system.24 The the individual risk of developing coronary artery plurimetabolic syndrome is the peculiar and, prob- disease frequently depends on the synergy of two or ably, most severe expression of an association that more risk factors, each often of only mild degree. cannot be considered as merely statistical.25 This implies that the calculated global risk is a more The present study was undertaken in order to powerful predictor of the cardiovascular outcome investigate whether cholesterol levels may affect BP than the individual risks from which it is 20,21 regulation independently of other well known deter- derived. Among the combinations of different minants such as age and body weight. For this rea- risk factors, the close relationship between arterial son we have measured BP not only at rest but also hypertension and abnormalities of lipid metabolism during 24-h monitoring and in response to an has been shown in epidemiological and genetic adrenergic stimulating test, the handgrip isometric 1,2,22 studies. Both serum cholesterol and triglyceride exercise. This is an easily performed marker of seem to be related to BP values and a possible link cardiovascular reactivity,26 which is well correlated between these conditions has been sought among with other tests of adrenergic stimulation27 and less

Journal of Human Hypertension Serum cholesterol affects blood pressure regulation LA Ferrara et al 341

Figure 2 Mean and peak thickness of the intima-media layer in 73 hypertensive patients divided according to tertiles of serum cholesterol levels (M ± s.e., signiﬁcance 1st vs other tertiles *P Ͻ 0.05). closely related to 24-h BP monitoring.8,27 Other thelial dysfunction in experimental31 and clinical investigations, such as those evaluating microneuro- studies, even at normal32 or high-to-normal3 ranges graphic neural activity, do indeed provide better by reducing the bioavailability of endothelium- indices of sympathetic function, but the advantage derived nitric oxide. Endothelium-dependent of the handgrip isometric exercise lies in its feasi- vasodilation, in fact, correlates inversely with total bility28 and intraobserver reproducibility.29 The cholesterol levels.3 Accordingly, lipid-lowering (ie main results of this clinical investigation indicate statins) and antihypertensive (ie, angiotensin- that BP levels at rest are not affected by serum chol- converting enzyme inhibitors) drugs improve or nor- esterol, contrarily to those in response to sympath- malise endothelial dysfunction33 (ie endothelium- etic stimulation, which more markedly increase in dependent vasodilation). These observations sup- patients with higher cholesterol levels, on the port the hypothesis that endothelium dysfunction opposite of HR response to handgrip, which was not may occur in relatively young individuals with mild different among tertiles. Accordingly hypertensive hypertension even at cholesterol levels considered patients with higher serum cholesterol also have a normal, as in the participants of the present study. thickening of the intima-media layer, which is a This is, probably, the reason of the lack of difference marker of a generalised arteriosclerotic disease.30 in BP response to handgrip between the second and The mass of the left ventricle, on the other hand, third tertiles, since cholesterol levels in the range does not seem to be affected by different choles- 5.2–5.9 mmol/L appear already able to induce alt- terol levels. ered endothelial function. The hypothesis that lipoproteins might be Finally it is possible that higher cholesterol levels relevant to hypertension is not new and is patho- may be associated with more atherosclerotic vessels, physiologically sound. In fact, they have direct not only in the carotid circulation, as shown in the stimulatory effects on both contraction-coupled and present paper by the increase of intima-media thick- replication-coupled processes in the vascular ness, but also in other arteries. Stiffer arteries, there- smooth muscle cells. These effects have been attri- fore, might be less able to counteract the increase in buted to the stimulation of the phosphoinositide sig- BP due to isometric exercise. Whatever the underly- nal transduction in smooth muscle cells.4 Moreover ing mechanism, it is conceivable that the effects of there is evidence that cholesterol induces endo- cholesterol levels on BP appear more evident in

Journal of Human Hypertension Serum cholesterol affects blood pressure regulation LA Ferrara et al 342 stressing situations, such as that induced by the 2 National Heart Foundation of Australia: risk factor handgrip-stimulated overactivity of the sympathetic prevalence study, report 1. National Heart Foundation nervous system. This finding is in agreement with a of Australia: Canberra, 1982. previous observation of the reduction in SBP 3 Vallance P, Collier J, Moncada S. Effects of endo- response to an arithmetic test in patients with high thelium-derived nitric oxide on peripheral arteriolar 34 tone in man. Lancet 1989; 2: 997–1000. cholesterol levels after lovastatin therapy. 4 Resink TJ et al. Interaction between plasma lipopro- With this purpose, the dissociation between BP teins and vascular smooth muscle cells: how relevant and HR response to handgrip in the tertiles of serum is it to arterial hypertension? Nutr Metab Cardiovasc cholesterol further support the hypothesis that Dis 1994; 4: 163–170. abnormal increase may be related to altered endo- 5 Creager MA et al. Impaired vasodilation of forearm thelium-dependent vasodilation. This discrepancy resistance vessels in hypercholesterolemic humans. J has already been seen in the above-mentioned study Clin Invest 1990; 86: 228–234. with a different adrenergic system stimulating test— 6 Clarkson P et al. Oral L-arginine improves endo- the arithmetic one—where lovastatin treatment was thelium-dependent dilation in hypercholesterolemic able to reduce SBP response, which depends on young adults. J Clin Invest 1996; 97: 1989–1994. 7 Johnson CJ, Kerr JH. Automatic blood pressure moni- endothelial damage, but not HR response, which 34 tors. A clinical evaluation of five models in adults. appears independent of it. Anesthesia 1985; 40: 471–478. The other main finding of this study—the increase 8 Floras JS, Osman Hassan M, Jones JV, Sleight P. in the IMT of the carotid artery—appears a natural Pressor responses to laboratory stresses and daytime consequence of the increase in the global risk of blood pressure variability. J Hypertens 1987; 5: 715– arteriosclerosis, determined by the concomitant 719. presence of mild hypertension and mild hyperchole- 9 Friedewald WT, Lery RI, Fredrickson DS. Estimation sterolaemia.30 To this purpose, it is useful to remem- of plasma low density lipoprotein cholesterol concen- ber that BP and serum cholesterol levels are posi- tration without use of the preparative ultracentrifuge. tively correlated with IMT in several studies.17,35,36 Clin Chem 1972; 18: 499–502. 10 Sahn DJ, De Maria A, Kisslo J, Weyman A. The Com- This finding is also in agreement with the results 37 mittee on M-Mode Standardization of the American of another study which demonstrated in Chinese Society of Echocardiography: recommendations patients the role of hypertension, hypercholesterola- regarding quantitation in M-Mode echocardiography. emia, and hypertrygliceridaemia in the pathogenesis Results of a survey of echocardiographic measure- of carotid atherosclerosis. ments. Circulation 1978; 58: 1072–1083. The lack of difference in LVM, which is mainly 11 Devereux RB, Reichek N. Echocardiographic determi- related to BP levels, depends on the similarities of nation of left ventricular mass in man. Anatomic vali- BP at rest and during 24-h measurement in the dation of the method. Circulation 1977; 55: 613–618. two subgroups. 12 de Simone G et al. Left ventricular mass and body size It is not unexpected that intima-media thickening in normotensive children and adults: assessment of allometric relations and impact of overweight. JAm does not parallel left ventricular (LV) hypertrophy Coll Cardiol 1992; 20: 1251–1260. in hypertensives, as already observed by ourselves 13 Teichholz LE, Kreulen T, Herman MV, Gorlin R. Prob- 17 in uncomplicated hypertensive patients. More lems in echocardiographic volume determinations: recently38 other authors stated that the relationship echocardiographic-angiographic correlations in the of BP variability with LV hypertrophy or carotid presence or absence of asinergy. Am J Cardiol 1976; damage is controversial and this finding may further 37:7–11. support the lack of correlation between ventricular 14 Wallerson DC, Ganau A, Roman MJ, Devereux RB. hypertrophy and carotid damage. Measurements of cardiac output by M-mode and two In conclusion the results of this study strongly dimensional echocardiography: application to patients support the hypothesis that even mildly increased with hypertension. Eur Heart J 1990; 11 (Suppl 1): 67–78. serum cholesterol levels are able to influence BP, at 15 Bond MG, Wilmoth SK, Enevold GL, Strickland HL. least during sympathetic stimulation. The relevance Detection and monitoring of asymptomatic athero- of this combination to the increase in global risk sclerosis in clinical trials. Am J Med 1989; 86 (Suppl and, therefore, to the early evidence of arterio- 4A): 33–36. sclerosis has also been pointed out by the present 16 Pignoli P et al. Intimal plus medial thickness of the investigation. arterial wall: a direct measurement with ultrasound imaging. Circulation 1986; 74: 1399–1406. 17 Ferrara LA et al. Early changes of the arterial carotid Acknowledgements wall in uncomplicated primary hypertensive patients. The authors are grateful to Mrs Rosanna Scala for Study by ultrasound high-resolution B-mode imaging. her linguistic revision. Arterioscler Thromb 1994; 14: 1290–1296. 18 Levy D et al. Echocardiographically detected left ventricular hypertrophy: prevalence and risk factors. The References Framingham Heart Study. Ann Int Med 1988; 108:7– 1 Laurenzi M et al, on behalf of the Gubbio Study Group. 13. Multiple risk factors in hypertension: results from the 19 Assmann G, Schulte H. The prospective cardiovascu- Gubbio Study. J Hypertens 1990; 8 (Suppl 1): S7–S12. lar Mu¨ nster (Procam) study: prevalence of hyperlipid-

Journal of Human Hypertension Serum cholesterol affects blood pressure regulation LA Ferrara et al 343 aemia in persons with hypertension and/or diabetes 29 Hamada M et al. Enhanced blood pressure response to mellitus and the relationship to coronary heart dis- isometric handgrip exercise with essential hyperten- ease. Am Heart J 1988; 116: 1713–1724. sion: effects of propanolol and razosin. J Hypertens 20 Prevention of coronary heart disease in clinical prac- 1987; 5: 305–309. tice. Recommendations of the Second Joint Task Force 30 Salonen JT, Salonen R. Ultrasonographically assessed of European and other Societes on coronary preven- carotid morphology and the risk of coronary artery dis- tion. Eur Heart J 1998; 19: 1434–1503. ease. Arterioscler Thromb 1991; 11: 1245–1249. 21 The International Task Force for prevention of coron- 31 Hayakawa H, Raij L. Relationship between hyper- ary heart disease in cooperation with the International cholesterolemia, endothelial dysfunction and hyper- Atherosclerosis Society. Coronary heart disease: tension. J Hypertens 1999; 17: 611–619. reducing the risk. The scientiﬁc background for pri- 32 Creager MA, Selwyn A. When ‘normal’ cholesterol mary and secondary prevention of coronary heart dis- levels injure the endothelium. Circulation 1997; 96: ease. A worldwide view. Nutr Metab Cardiovasc Dis 3255–3257. 1998; 8: 205–271. 33 Nazzaro P et al. Distinct and combined vascular effects 22 Williams RR et al. Familial dyslipidemic hyperten- of ACE blockade and HMG – CoA reductase inhibition sion. Evidence from 58 Utah families for a syndrome in hypertensive subjects. Hypertension 1999; 33: present in approximately 12% of patients with essen- 719–725. 34 Sung BH, Izzo JL, Wilson MF. Effects of cholesterol tial hypertension. JAMA 1988; 259: 3579–3586. reduction on BP response to mental stress in patients 23 Ferrannini E et al. Insulin resistance in essential with high cholesterol. Am J Hypertens 1997; 10: hypertension. N Engl J Med 1987; 317: 350–357. 592–599. 24 Hunt SC, Williams RR, Smith JB, Ash KO. Associ- 35 Poli A et al. Ultrasonographic measurement of the ations of three erythrocytes cation transport system common carotid artery wall thickness in hypercholest- with plasma lipids in Utah subjects. Hypertension erolemic patients. Atherosclerosis 1988; 70: 253–261. 1986; 8:30–36. 36 Heiss G et al, and the ARIC Investigators. Carotid 25 Reaven GR. Role of insulin resistance in human dis- atherosclerosis measured by B-mode ultrasound in ease. Diabetes 1988; 37: 1595–1607. populations: associations with cardiovascular risk fac- 26 Musgrave IF, Bachmann AW, Saar N, Gordon RD. A tors in the ARIC Study. Am J Epidemiol 1991; 134: comparison of cardiovascular and catecholamine 250–256. responses to three stimuli in mild hypertension. 37 Pan WH, Bai CH, Chen JR, Chiu HC. Associations Metabolism 1984; 33: 718–723. between carotid atherosclerosis and high factor VIII 27 Guida L et al. Clinic-daytime blood pressure difference activity, dyslipidemia, and hypertension. Stroke 1997; and cardiovascular damage. J Hypertens 1999; 17: 28:88–94. 331–337. 38 Roman MJ et al. Relation of blood pressure variability 28 Ferrara LA et al. Olive oil and reduced need for antihy- to carotid atherosclerosis and carotid artery and left pertensive medications. Arch Intern Med 2000; 160: ventricular hypertrophy. Arterioscler Thromb Vasc 837–842. Biol 2001; 21: 1507–1511.

Journal of Human Hypertension