Journal of Human Hypertension (2002) 16, 753–760 & 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh REVIEW ARTICLE Lipid lowering: another method of reducing blood pressure?

AS Wierzbicki Lipid Unit, Department of Chemical Pathology, St Thomas’ Hospital, London, UK

Modern management of cardiovascular risk depends on pulse wave velocity. This blood pressure action may assessment of cardiovascular risk factors. Hypertension account for some of the clinical effects of lipid-lowering and hyperlipidaemia are synergistic risk factors for drugs on cardiovascular risk. Thus, lipid lowering may cardiovascular events. Both show a degree of cross- provide an additional method of correcting hypertension correlation through sharing mechanisms of pathogen- in some high-risk patients. However, data from large- esis including insulin resistance and endothelial dys- scale intervention trials are either absent or ambiguous. function. This article reviews the common pathways Definitive large-scale trials to investigate the antihyper- leading to dyslipidaemia and hypertension and the tensive effects of lipid-lowering drugs are required, effects diet and lipid-lowering drug therapies have had although end point studies examining the interaction of on correcting blood pressure in patients with essential lipid-lowering and antihypertensive drugs to determine hypertension. Both statins and fibrates have shown a optimum combinations are already under way. capability to lower blood pressure by up to 8/5 and 15/ Journal of Human Hypertension (2002) 16, 753–760. 10 mmHg respectively, in some small-scale clinical trials doi:10.1038/sj.jhh.1001483 and have effects on arterial wall structure and hence

Keywords: cholesterol; cardiovascular risk; statin; fibrate; review; hypertension

Introduction obese.2–4 In secondary hypertension, disorders asso- ciated with chronic renal failure cause a mixed Hyperlipidaemia and hypertension are common hyperlipidaemia or, in the case of nephrotic syn- conditions that both contribute synergistically to drome, hypercholesterolaemia.3 Hypertension and cardiovascular risk. The management of cardiovas- hyperlipidaemia may be related at a deeper level as cular risk now forms the principal function of both insulin resistance is a common feature in the lipid and hypertension clinics, and this article will pathogenesis of both conditions.5,6 In epidemiologi- address what benefits over and beyond risk reduc- cal studies, where hypertension has been linked to tion can be achieved by management of the causes of hyperlipidaemia, the principal factors seem to be hyperlipidaemia and, in particular, whether lipid- insulin resistance and saturated fat intake (ie plasma lowering drugs have direct effects on blood pressure. cholesterol) (Table 1).7 Endothelial dysfunction has been described in association with hypertension in many studies; it also has strong associations with Epidemiology insulin resistance, dyslipidaemia, and other cardio- vascular risk factors.8 Indeed, hypertension and Surveys of hypertensive patients routinely identify hypercholesterolaemia act synergistically as cardio- other cardiovascular risk factors in this population. vascular risk factors, although the exact mechanisms If lipids have effects in blood pressure, it would be are obscure but certainly include both insulin expected that patients with hyperlipidaemia would resistance and endothelial dysfunction. show a greater incidence of hypertension. The common occurrence of both syndromes is often noted but, given the high prevalence of both Dietary management hyperlipidaemia and hypertension, is often dismissed as coincidental.1 Up to 40% of hyperten- Lifestyle strategies are employed in the management sive patients have hyperlipidaemia and 40% are of both hyperlipidaemia and hypertension, and both diets have remarkable similarities. Both aim to stop smoking, reduce saturated fat intake, reduce alcohol Correspondence: AS Wierzbicki, Department of Chemical Pathol- consumption, increase fruit and fibre intake, and ogy, St. Thomas’ Hospital, Lambeth Palace Road, London SE1 6 7EH, UK. improve exercise tolerance. The only difference is Received 13 March 2002; revised and accepted 2 September 2002 in the salt restriction, which is not routinely advised Lipid lowering and blood pressure AS Wierzbicki

754 Table 1 Epidemiological studies that have identified links between hypertension and hypercholesterolaemia. After Goode et al7 Study Numbers Lipid factors Possible pathology Tecumseh Community 3064 TC, TG IRS, saturated fat Southern California 4839 TC, TG IRS, saturated fat Framingham 5127 TC Saturated fat Tromso 16 744 TC, LDL, VLDL-C IRS, saturated fat LRC prevalence 7747 TG, VLDL-C IRS Williams 6128 LDL Saturated fat

Abbreviation: total cholesterol (TC); triglyceride (TG); low-density-lipoprotein cholesterol (LDL-C); very-low-density-lipoprotein cholesterol (VLDL-C); insulin resistance syndrome (IRS).

for patients with hyperlipidaemia. Diet remains over and above low HDL, and apolipoprotein C2 in controversial in the management of hyperlipidaemia men.17 In the Utah study, which included patients as many intervention trials have shown only mini- with familial combined hyperlipidaemia (FCH) mal effects on the surrogate endpoint of cholesterol and familial hypercholesterolaemia (FH), SLC reduction. Yet trials with polyunsaturated fatty activity also correlated strongly with blood acids achieve a 0.6 mmol/l reduction in cholesterol pressure and lipids.18,19 Both these epidemiological as opposed to 0.15–0.3 mmol/l achieved with low- studies linked SLC to triglycerides, insulin cholesterol diet.9 The Mediterranean diet as used in resistance, and lipoprotein lipase activity as have 605 patients in the Lyons Diet Heart Study10 or studies in patients with type V hyperlipidaemia.20 polyunsaturated fatty acid supplements used in The Utah study population defined a subgroup GISSI-P in 11 374 patients11 showed reductions in of up to 10% of patients with essential hypertension coronary events of 40–70 and 20%, respectively. The who had a phenotype of dyslipidaemia allied role of diet in hypertension is also controversial with hypertension with a strong genetic component. though again many studies show a reduction in This group was termed familial dyslipidaemic blood pressure of 5 mmHg with diets rich in hypertension (FDH). Studies in patients with polyunsaturated fatty acids, which did not translate FCH have persistently shown the presence of into significant benefits in coronary events or hypertension in 30–40% of patients, suggesting a strokes probably due to the inadequate size of the lower penetrance for hypertension compared to studies.12 The most recent of these was the dietary dyslipidaemia in this group.21 Recently, a study in approaches to the hypertension study (DASH) in a colony of 634 baboons colony localised the gene 459 patients with a blood pressure 4160/80 mmHg, behind SLC activity to baboon chromosome 5, a which showed reductions of 11.6/5.3 mmHg in homologue of human chromosome 4.22 Genetic hypertensive patients as opposed to 3.5/2 mmHg in mapping studies of hypertension in FCH kindreds nonhypertensive patients with a low-cholesterol also show quantitative trait linkage of SLC activity and low-salt diet.13 to human chromosome 4p in the region containing a fatty acid hydrolase (CD36) and a-adducin and secondary loci at chromosome 8p near the Sodium–lithium countertransport and familial lipoprotein lipase gene and for diastolic blood dyslipidaemic hypertension pressure chromosome 19 close to the apolipoprotein B locus.21 Many, but not all, studies, have shown Surrogate markers for hypertension have been an association between a-adducin polymorphisms defined. The most currently investigated are the and hypertension in cross-sectional studies23 and a effects of hyperlipidaemia on nitric oxide produc- few have implicated the fatty acid hydrolase tion and paracrine hormone production by the CD 36.24 endothelium (vide infra). However, other markers These studies suggest that a subgroup of patients also show a relationship between hyperlipidaemia with essential hypertension are also dyslipidaemic. and hypertension. Sodium–lithium countertran- This may comprise up to 10% of patients with sport is an ill-understood membrane transport hypertension. The treatment of FCH is well estab- marker associated with hypertension and insulin lished with the use of statins, fibrates, or often a resistance.14,15 It has been shown to be a prospective combination of both. However, no studies have marker for hypertension in the Gubbio study.16 The measured the blood pressure response to lipid- kinetics of SLC activity show similar correlations lowering therapy using accurate methods in this with ethnicity, hypertension, and cardiovascular patient group. risk.14 Sodium–lithium countertransport is highly ge- netically inherited and shows a 65–80% heritability Endothelium and hyperlipidaemia in various cohort studies.14 The Rochester study of 900 patients showed that SLC activity modelled as a The interaction of lipids and the endothelium has recessive monogenic trait predicted blood pressure been extensively reviewed in many publications,

Journal of Human Hypertension Lipid lowering and blood pressure AS Wierzbicki

755 and shows a strong relationship between endothe- decrease in albuminuria was seen in patients with lial function and cholesterol or oxidised cholesterol nephrotic syndrome with fibrate therapy compared levels.25,26 Although the direct role of endothelial with a 2% decrease with a statin.35 Statin therapy dysfunction in determining prognosis in cardiovas- reduced microalbuminuria and endothelin levels in cular disease remains to be fully confirmed, increas- 60 patients with type II diabetes.36 However, in ing circumstantial evidence has confirmed that neither study was blood pressure significantly endothelial dysfunction is a feature of patients with affected and it has been assumed that these were hypertension and also those with diabetes, insulin endothelial actions of lipid lowering. Other studies resistance and small, dense LDL, hypercholestero- using apheresis have shown no difference in laemia, homocysteinaemia, but interesting not gross proteinuria. A trial is under way in 864 patients to hypertriglyceridaemia. The lack of endothelial dys- examine the effect of statins in addition to ACE- function in type V hyperlipidaemia despite severe inhibitors on microalbuminuria.37 There are no data insulin resistance cannot be easily explained.27 on the effect of lipid-lowering therapy on hyperten- Any treatment of hyperlipidaemia including diet, sive retinopathy. bile acid sequestrants, statins, and fibrates improves In contrast, left ventricular hypertrophy (LVH) is endothelial function.26 Many studies with statins associated with hypertension and also insulin have demonstrated improvements in endothelial resistance syndromes including high triglycerides function that can occur within 2 weeks.28,29 Simi- allied with low HDL.38–40 Few studies of lipid- larly, fibrates improve endothelial function in lowering therapy have been performed, although patients with diabetes through actions on post- one study using echocardiographic methods did prandial lipaemia and HDL.30 However, little effect show a 10% decrease in LVH with pravastatin was seen on blood pressure in any of these studies. therapy in 25 patients.41 The effect of statins on The mechanism by which lipid lowering increases LVH seems to be mediated by isoprenoid intermedi- nitric oxide production probably involves recou- ates and interference with the action of angiotensin- pling of endothelial nitric oxide synthase to enhance 2. Expression and sensitivity of the angiotensin-2 the production of nitric oxide rather than the type 1 receptor, whose activation is involved in the peroxynitrite production associated with the de- pathogenesis of LVH, is proportional to plasma LDL; coupled enzyme and reduction of angiotensin II so an effect of statins is not surprising.31,42 There are receptor expression.31 How directly endothelial no data on other lipid-lowering drugs, although the function relates to blood pressure is controversial32 relationship between low HDL and LVH suggests because though cholesterol concentration correlates that fibrates might have greater effects on LVH. well with endothelial function the studies examin- ing the relationship between endothelial function and blood pressure have been conflicting. Some Pulse wave analysis and lipid-lowering studies using flow-mediated dilation have shown an therapy association of endothelial function with hyperten- sion while others using brachial plethysmography Nitric oxide also plays a critical role in the paracrine have either failed to show any relationship or show autoregulation of blood flow and hence in the a mild association.33 Given the conflicting data on determination of the peripheral resistance compo- the endothelial actions of some antihypertensive nent of blood pressure. The primary role of pulse drugs, it remains to be seen whether concomitant pressure as the principal determinant behind hy- therapy with lipid-lowering drugs will be synergis- pertension-associated cardiovascular risk in the tic or antagonistic. older patients has recently been demonstrated using The main criticism of these studies investigating data from the Framingham cohort.43 Pulse pressure the role of lipid-lowering drugs on endothelial augmentation occurs as a result of speedier pulse function as a surrogate for blood pressure is that wave reflection in stiffer arteries and gives rise to the the blood pressure response over the study period is characteristic isolated systolic hypertension of the not usually quoted or accurately measured. elderly.44–46 Numerous studies have shown an association of pulse wave velocity as measured by Doppler ultrasound techniques with hypertension Hypertension-associated target-organ and cardiovascular risk.47–49 Similarly, there is an damage and lipid-lowering drugs association of reduced arterial compliance with cardiovascular risk and hypertension. Recent stu- Microalbuminuria, retinopathy, and left ventricular dies using portable pulse wave analysis machines hypertrophy are measured as indices of target-organ derive pulse wave velocity or analogous measures damage.34 Microalbuminuria is an index of renal (eg stiffness index) mathematically from the pulse glomerular endothelial function, and numerous waveform and, similarly, the extent of augmentation studies have documented the effects of antihyper- (augmentation/reflection index) of peripheral blood tensives, ACE-inhibitors, or angiotensin-2 anta- pressure.46 Recent cohort studies show that pulse gonists on microalbuminuria in diabetic and wave velocity is a 2.3-fold independent risk factor nondiabetic (ie hypertensive) populations. A 4% above the Framingham study-derived parameters for

Journal of Human Hypertension Lipid lowering and blood pressure AS Wierzbicki

756 cardiovascular events in a prospective hypertension hyperlipidaemia are seen with PPAR-gamma ago- cohort study.47 Pulse wave velocity is altered by any nists (thiazolidinediones) or metformin; so an effect agent altering blood pressure and also by lipid- of fibrates on blood pressure might be predicted but lowering drugs, suggesting that if arterial stiffness is there are no large-scale studies. an index of hypertension and atherosclerosis then With statins data are currently scarce (Table 2), lipid-lowering drugs should have profound effects on but small-scale studies showed a reduction in the hypertension. One study of 22 patients with isolated hypertensive response to mental stress in hyperli- systolic hypertension treated with 80 mg atorvastatin pidaemic patients and a nonsignificant decrease in has examined this.50 It showed a 6/2 mmHg fall in blood pressure of 3 mmHg with lovastatin in 26 electronically measured blood pressure, and in- patients.59 Other studies with fluvastatin in 49 creased vascular compliance from 0.37 to 0.43 ml/ patients and 23 patients, respectively, showed mmHg with a 48% reduction in LDL. Larger scale significant reductions in blood pressure (6/3 mmHg) studies are required to confirm these findings. after 6 weeks.60,61 One of these studies showed a clear correlation of blood pressure response with elevation in nitric oxide production. Similarly, Lipid-lowering drugs and blood pressure pravastatin blunted the pressor effects of angioten- The topic of blood pressure effects of lipid-lowering sin II and noradrenaline on diastolic blood pressure in a trial in seven patients.62,63 Other reports show drugs has been reviewed previously and informa- 64 tion is limited (Table 2).7 Data from the older no or nonsignificant responses to statin therapy. A cardiovascular prevention trials using bile acid randomised double-blind crossover trial of pravas- sequestrants (Lipids Research Clinics (LRC) study)3 tatin 20–40 mg in 30 patients with moderate hyper- and fibrates (WHO clofibrate trial)55 are negative, lipidaemia and hypertension showed a reduction of although the incidence of new hypertension was 8/5 mmHg in blood pressure, blunting in the cold pressor test response and reduction in plasma decreased by 25% over the course of the LRC study. 64 Data are not available from any of the other studies endothelin-1 levels. However, to date, there are using bile acid sequestrants or fibrates, for example, no large studies using automated measurement of Helsinki Heart Study. blood pressure, which improves standardisation, However, some recent reports are intriguing. The and no large studies that have examined the effects Air Force Regression with Gemfibrozil Study (AF- of lipid lowering using 24 h ambulatory monitoring. REGS), a coronary regression study with the gemfi- Long-term data beyond 3 months are also lacking. brozil, presented at the American Heart Association Thus the data to date, although limited by small in 1998 showed a 12/6 mmHg reduction in blood numbers, tend to suggest that statins may also lower pressure with expected effects on progression of blood pressure at least over a short time scale. stenosis. The magnitude of the blood pressure effect matched that seen in a study of the effects of fibrate Trial evidence therapy on insulin resistance (14.7/9.8 mmHg).56 Reductions in blood pressure through actions on Early meta-analyses of the results of trials of insulin resistance and through lesser effects on antihypertensive therapy in coronary and cerebro-

Table 2 Intervention studies on hypercholesterolaemia that have shown effects on blood pressure, extended after Goode et al7 Study Numbers BP treated Method Follow-up Intervention LDL BP (months) Baseline D (mmol/l) Baseline D (mmHg) (mmol/l) (mmHg) Leiden51 39 n Hg 24 Diet 4.70 0.7 130/84 4.2/2.4 POSCH52 838 y Hg 120 Ileal bypass 4.29 1.5 124/81 4.0/2.0 LRC53 3806 y Hg 84 Cholestyramine 5.20 0.7 124/84 0.0/2.0 PVD54 24 y Hg 24 Resin+clofibrate 5.41 1.5 151/89 6.0/2.0 WHO55 5000 y Hg 84 Clofibrate 4.50 0.6 120/80 0a AF-REGS 150 y Hg 12 Gemfibrozil 3.65 0.2 136/85 12.0/8.0 Idzior-Walus56 37 n Hg 1.5 Fenofibrate 4.48 0.53 145/90 14.7/9.8 Morgan57 49 y Hg 3 Simvastatin 4.60 2.0 128/87 5.2/3.5 Atarashi 16 y Hg 6 Pravastatin 3.60 1.1 134/88 3.9/0.0 EXCEL58 8245 y Hg 11 Lovastatin 4.65 1.03–2.06 128/88 1.3/0.7 Sung59 26 y Hg 1.5 Lovastatin 4.68 1.2 120/80 3.0/0.0 Jarai60 49 n Hg 3 Fluvastatin 5.13 1.18 145/95 5.0/2.0 Abetel61 23 n ABPM 3 Fluvastatin 5.63 1.0 147/100 4.0/2.0 Glorioso64 30 n ABPM 8 Pravastatin 4.31 1.09 149/97 8.0/5.0 Ferrier50 22 n E 3 Atorvastatin 3.40 1.53 154/82 6.0/2.0

a25% reduction in new hypertension. Abbreviations: Program on Surgical Correction of Hyperlipidaemia (POSCH); peripheral vascular disease (PVD); World Health Organization (WHO); Air Force Regression with Gemfibrozil Study (AF-REGS); expanded clinical evaluation of lovastatin (EXCEL); sphygmomanometric blood pressure (Hg); electronic blood pressure (E); ambulatory blood pressure monitoring (ABPM).

Journal of Human Hypertension Lipid lowering and blood pressure AS Wierzbicki

757 vascular disease suggest that a 30% reduction in mic’ patients. Most of the benefit related to a 30% stroke and a 10% reduction in coronary heart reduction in strokes and carotid endarterectomies disease can be achieved with a 5 mmHg reduction with little difference in coronary intervention rates. in systolic blood pressure.65 Although many end- Blood pressure data are not yet available from this point trials have been performed using antihyper- study with regard to outcomes, but the predominant tensive drugs, the uptake of lipid-lowering therapy reductions in stroke are intriguing if fibrates have in these trials has been small (o10%) and subgroup major antihypertensive effects.56 analyses with lipid-lowering agents have not been Subgroup analyses of statin trials also indicate a published. More recent meta-analyses suggested 20–30% reduction in stroke in the secondary that reducing blood pressure by 15/6 mmHg will prevention trials. However, detailed data on the reduce stroke by 50% in young patients and by 34% exact groups of antihypertensive drugs were not in the elderly.66 Large-scale endpoint studies in the available, although a high usage of thiazide diuretics field of hyperlipidaemia show clear evidence of was likely. Additionally, beta-blockers were used in mortality benefit with cholesterol reduction. The 40–55% of secondary prevention patients for trials in question have mostly used statins: the post-infarct benefits independent of blood pressure. Scandinavian Simvastatin Survival Study (4S),67 Initial analyses of the data from these studies Cholesterol and Recurrent Events (CARE),68 Lipid showed little difference in relative risk reduction Intervention with Pravastatin in Ischemic Disease between the ‘hypertensive’ and ‘normotensive’ (LIPID)69 in secondary prevention and the primary groups. The pooled analysis of the Pravastatin prevention West Of Scotland Coronary Prevention Atherosclerosis Intervention Project (PAIP) trials of Study (WOSCOPS),70 and the Air Force Texas high-risk patients showed an additional 12% Coronary Artery Prevention Study (AF-Tex CAPS)71 risk reduction (69 vs 57%) in patients with hyper- have undergone subgroup analysis with respect to tension in an analysis of 1891 patients.74 However, hypertension. Lipid lowering had the same relative the prespecified pooled analysis of the pravastatin risk reduction in the hypertensive as nonhyperten- trials including 19 768 patients showed that sive patients in these studies. In terms of cardiovas- pravastatin therapy had a greater effect on absolute cular risk, evidence of benefit has been shown to risk in patients without hypertension than in extend between 1.2 and 5%/year risk of coronary hypertensive individuals (33 vs 14%; p ¼ 0.003). events. There is no heterogeneity between statin This effect was dependent on study selection, studies, but as patients with hypertension have but independent of baseline risk factors and greater absolute risk of cardiovascular events then medications, although data on doses and combina- statins have a greater effect on cardiovascular events tions of antihypertensives were not analysed. It was in patients with hypertension. Whether this effect is noted that pravastatin therapy seemed to have no solely due to lipid lowering or to any additional effect on blood pressure in any of the studies.75 This effects on blood pressure is uncertain. In stroke finding cannot easily be explained, but the role of there is only a weak relationship between LDL- final LDL values achieved on therapy was not cholesterol and risk of events, but the principal risk considered and might account for the difference. factors are age and hypertension or pulse pressure. Data are not available from the 4S study, but that is Statins reduce cardiovascular events and also stroke likely to be confounded by higher usage of beta- through plaque stabilisation. It is interesting to note blockers (55 vs 40%) and lower usage of aspirin (50 that a fall in shear stress due to a fall in blood vs 80%) than the pravastatin trials.67 Trials with pressure will benefit endothelial function and some other agents have been too small to allow any effects of the action of statins may occur through this on blood pressure to be determined. The question mechanism. remains to be answered of whether the benefit in One fibrate trial has recently been published. The reduction of strokes and TIAs seen in statin trials Veterans Administration HDL Intervention Trial with pravastatin and simvastatin and the trend (VA-HIT) studied 2200 secondary prevention pa- towards a reduction in heart failure events tients with low HDL (0.88 mmol/l) and low LDL (p ¼ 0.08) seen in the Cholesterol And Recurrent (3.0 mmol/l/l) (Table 1).72 The intervention was Events (CARE) study could be related to effects on 1200 mg of gemfibrozil, which had previously blood pressure as part of any effect on plaque shown benefit in arteriographic regression studies stabilisation.76 Certainly, the effects of statins on but failed to demonstrate a reduction in mortality as stroke are easily expressed by the magnitude of a opposed to coronary events in the Helsinki Heart blood pressure change if it followed that seen in the Study. A secondary prevention study in 6000 small-scale trials. Similarly, in hydrodynamic terms, patients with bezafibrateFthe Bezafibrate Infarct a reduction in blood pressure would lead to a Prevention Study (BIPS)Falso failed to demonstrate reduction in shear stress and hence improvement in any event or mortality benefit except in the endothelial function and increased plaque surface hypertriglyceridaemic low-HDL subgroup.73 In VA- stability. Could some of the vaunted ‘non-lipid HIT a 22% reduction in a composite event endpoint lowering’ actions of statins simply be due to effects was achieved without any effect on LDL, and the on blood pressure? As yet there are no studies to benefit was similar in diabetics and ‘normoglycae- answer these questions.

Journal of Human Hypertension Lipid lowering and blood pressure AS Wierzbicki

758 Studies are required that compare the efficacy of 3 Criqui MH et al. Frequency and clustering of non-lipid different classes of antihypertensive combined with cardiovascular risk factors in dyslipoproteinemia: the lipid lowering to confirm whether lipid lowering is Lipids Research Clinics Program Prevalence Study. beneficial when added to blood pressure reduction. Circulation 1986; 73: I-40–I-50. A study of 35 patients combining lisinopril with 4 Criqui MH et al. Clustering of cardiovascular disease risk factors. Prevent Med 1980; 9: 523–526. lovastatin showed a greater effect in patients of ACE- 5 Kannel WB, Wilson PW, Zhang TJ. The epidemiology inhibitor in patients on statin (18 vs 12%; po0.05) of impaired glucose tolerance and hypertension. Am 77 than in a group not receiving treatment. Large Heart J 1991; 121: 1268–1273. studies are required to define any particularly 6 Hopkins PN et al. Hypertension, dyslipidaemia and favourable or deleterious combinations as lipid- insulin resistance: links in a chain or spokes on a lowering and antihypertensive therapies are often wheel? Curr Opin Lipidol 1996; 7: 241–253. prescribed simultaneously. Two such studies are 7 Goode GK, Miller JP, Heagerty AM. Hyperlipidaemia, under way. The Antihypertensive and Lipid Low- hypertension, and coronary heart disease. Lancet 1995; ering Treatment to Prevent Heart Attack Trial 345: 362–364. (ALLHAT) of 70 000 patients compares thiazides, 8 Castelli WP, Anderson A. A population at risk; prevalence of high cholesterol levels in hypertensive beta-blockers, calcium channel blockers, alpha patients in the Framingham Study. Am J Med 1986; 80: antagonists, and ACE-inhibitors in patients with 23–32. 78,79 primary hypertension (4160/95 mmHg). Addi- 9 Law MR, Wald NJ, Thompson SG. By how much and tional randomisation is performed with 40 mg how quickly does reduction in serum cholesterol pravastatin or placebo. Similarly the Anglo-Scandi- concentration lower risk of ischaemic heart disease? navian Cardiac Outcomes (ASCOT) study examines BMJ 1994; 308: 367–372. four drug classes with atorvastatin in 4000 patients 10 de Lorgeril M et al. Mediterranean diet, traditional risk at moderate risk of atheromatous events.80 factors and the rate of cardiovascular complications after myocardial infraction: final report of the Lyon Diet Heart Study. Circulation 1999; 99: 733–736. 11 GISSI-Prevenzione Investigators. Dietary supplemen- Conclusions tation with n-3 Polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the Total atherosclerotic risk factor management is GISSI-Prevenzione trial. Lancet 1999; 354: 447–455. increasingly necessary to treat fully the burden of 12 Nordoy A, Marchioli R, Arnesen H, Videbaek J. n-3 atherosclerotic disease and a variety of its manifes- Polyunsaturated fatty acids and cardiovascular dis- tations. The latest guidelines from international eases. Lipids 2001; 36(Suppl): S127–S129. 13 Sacks FM et al. Effects on blood pressure of reduced associations including the Joint European Societies, dietary sodium and the dietary approaches to stop Joint British Societies, and New Zealand guidelines hypertension (DASH) diet. DASH-Sodium Collabora- and National Cholesterol Education Program stress tive Research Group. N Engl J Med 2001; 344: the role of total risk management in patients with 3–10. atheroma. Thus, blood pressure and cholesterol are 14 Hardman TC, Lant AF. Controversies surrounding viewed as individually uninformative unless indi- erythrocyte sodium–lithium countertransport. J Hyper- cative of severe primary disease, for example tens. 1996; 14: 695–703. malignant hypertension, hypertension with target- 15 Hardman TC, Dubrey SW, Soni S, Lant AF. Relation of organ damage, or familial hypercholesterolaemia or sodium–lithium countertransport activity to markers other familial hyperlipidaemias. Lipid-lowering of cardiovascular risk in normotensive subjects. J Hum Hypertens 1995; 9: 589–596. drugs have traditionally been viewed as only 16 Cirillo M et al. Prospective analysis of traits related to addressing a subset of cardiovascular risk factors 6-year change in sodium–lithium countertransport. and to have little effect on hypertension. This article Gubbio Population Study Research Group. Hyperten- has reviewed the evidence that lipid-lowering drugs sion 1999; 33: 887–893. may, by their direct methods of action, be anti- 17 Rebbeck TR, Turner ST, Michels VV, Moll PP. Genetic hypertensive and may at least modulate blood and environmental explanations for the distribution of pressure. Data are now needed from large scale sodiumFlithium countertransport in pedigrees from studies to ascertain which are the optimal combina- Rochester, MN. Am J Hum Genet 1991; 48: 1092–1104. tions of blood-pressure-lowering drugs and lipid- 18 Williams RR et al. Sodium–lithium countertransport in lowering drugs to treat individual patient groups. erythrocytes of hypertension prone families in Utah. Am J Epidemiol 1983; 118: 338–344. 19 Hunt SC et al. A prospective study of sodium–lithium countertransport and hypertension in Utah. Hyperten- References sion 1991; 17: 1–7. 20 Wierzbicki AS et al. Relation between sodium–lithium 1 Bonaa KH, Thelle DS. Association of blood pressure countertransport and hypertriglyceridemia in type V and serum lipids in a population: the Tromso study. hyperlipidemia. Am J Hypertens 2001; 14: 32–37. Circulation 1991; 83: 1305–1314. 21 Allayee H et al. Genome scan for blood pressure 2 Ostrander LD, Lamphiear DE. Coronary risk factors in Dutch dyslipidemic families reveals linkage to a in the community: findings in Tecumseh, Michigan. locus on chromosome 4p. Hypertension 2001; 38: Circulation 1976; 53: 152–156. 773–778.

Journal of Human Hypertension Lipid lowering and blood pressure AS Wierzbicki

759 22 Kammerer CM et al. Sodium–lithium countertransport 39 Kannel WB. Influence of multiple risk factors on the activity is linked to chromosome 5 in baboons. hazard of hypertension. J Cardiovasc Pharmacol 1990; Hypertension 2001; 37: 398–402. 16(Suppl 5): S53–S57. 23 Bianchi G, Cusi D. Association and linkage analysis of 40 Schillaci G et al. High-density lipoprotein cholesterol alpha-adducin polymorphism: is the glass half full or and left ventricular hypertrophy in essential hyperten- half empty? Am J Hypertens 2000; 13: 739–743. sion. J Hypertens 2001; 19: 2265–2270. 24 Pravenec M et al. Genetic analysis of cardiovascular 41 Su S et al. Effects of pravastatin on left ventricular mass risk factor clustering in spontaneous hypertension. in patients with hyperlipidemia and essential hyper- Folia Biol (Krakow) 2000; 46: 233–240. tension. Am J Cardiol 2000; 86: 514–518. 25 Celermajer DS et al. Non-invasive detection of en- 42 Nickenig G et al. Statin-sensitive dysregulated AT1 dothelial dysfunction in children and adults at risk of receptor function and density in hypercholesterolemic atherosclerosis. Lancet 1992; 340: 1111–1115. men. Circulation 1999; 100: 2131–2134. 26 Celermajer DS. Endothelial dysfunction: does it mat- 43 Franklin SS et al. Does the relation of blood pressure to ter? Is it reversible? J Am Coll Cardiol 1997; 30: coronary heart disease risk change with aging? The 325–333. Framingham Heart Study. Circulation 2001; 103: 27 Chowienczyk PJ et al. Preserved endothelial function 1245–1249. in patients with severe hypertriglyceridemia and low 44 O’Rourke MF. Wave travel and reflection in the arterial functional lipoprotein lipase activity. J Am Coll system. J Hypertens. 1999; 17 (Suppl 5): S45–S47. Cardiol 1997; 29: 964–968. 45 Wilkinson IB, Cockcroft JR, Webb DJ. Pulse wave 28 Simons LA, Sullivan D, Simons J, Celermajer DS. analysis and arterial stiffness. J Cardiovasc Pharmacol Effects of atorvastatin monotherapy and simvastatin 1998; 32(Suppl 3): S33–S37. plus cholestyramine on arterial endothelial function in 46 O’Rourke MF, Pauca A, Jiang XJ. Pulse wave analysis. patients with severe hypercholesterolaemia. Athero- Br J Clin Pharmacol 2001; 51: 507–522. sclerosis 1998; 132: 197–203. 47 Meaume S et al. Aortic pulse wave velocity as a marker 29 Stroes ESG, Koomans HA, de Bruin TWA, Rabelink TJ. of cardiovascular disease in subjects over 70 years old. Vascular function in the forearm of hypercholester- J Hypertens 2001; 19: 871–877. olemic patients off and on lipid-lowering medication. 48 Blacher J et al. Aortic pulse wave velocity as a marker Lancet 1995; 346: 467–471. of cardiovascular risk in hypertensive patients. Hyper- 30 Evans M et al. Ciprofibrate therapy improves endothe- tension 1999; 33: 1111–1117. lial function and reduces postprandial lipemia and 49 Asmar R et al. Pulse pressure and aortic pulse wave are oxidative stress in type 2 diabetes mellitus. Circulation markers of cardiovascular risk in hypertensive popula- 2000; 101: 1773–1779. tions. Am J Hypertens 2001; 14: 91–97. 31 Wassmann S et al. HMG-CoA reductase inhibitors 50 Ferrier KE et al. Intensive cholesterol reduction lowers improve endothelial dysfunction in normocholester- blood pressure and large artery stiffness in isolated olemic hypertension via reduced production of reac- systolic hypertension. J Am Coll Cardiol 2002; 39: tive oxygen species. Hypertension 2001; 37: 1450– 1020–1025. 1457. 51 Arntzenius AC et al. Diet, lipoproteins, and the 32 Schiffrin EL. A critical review of the role of endothelial progression of coronary atherosclerosis. The Leiden factors in the pathogenesis of hypertension. J Cardio- Intervention Trial. N Engl J Med 1985; 312: 805–811. vasc Pharmacol 2001; 38 (Suppl 2): S3–S6. 52 Buchwald H et al. Changes in sequential coronary 33 Cockroft JR, Chowienczyk PJ, Ritter JM. Hyperlipidae- arteriograms and subsequent coronary events. Surgical mia, hypertension and coronary heart disease. Lancet Control of the Hyperlipidemias (POSCH) Group. JAMA 1995; 345: 862–863. 1992; 268: 1429–1433. 34 Pedrinelli R et al. Microalbuminuria and pulse pres- 53 The Lipid Research Clinics Coronary Primary Preven- sure in hypertensive and atherosclerotic men. Hyper- tion Trial results. I. Reduction in incidence of coronary tension 2000; 35: 48–54. heart disease. JAMA 1984; 251: 351–364. 35 Deighan CJ et al. Comparative effects of cerivastatin 54 Duffield RG, Miller NE, Jamieson CW, Lewis B. A and fenofibrate on the atherogenic lipoprotein pheno- controlled trial of plasma lipid reduction in peripheral type in proteinuric renal disease. J Am Soc Nephrol atherosclerosisFan interim report. Br J Surg 1982; 2001; 12: 341–348. 69(Suppl): S3–S5. 36 Nakamura T et al. Effect of cerivastatin on urinary 55 Committee of Principal Investigators. A co-operative albumin excretion and plasma endothelin-1 concen- trial of primary prevention of ischaemic heart disease trations in type 2 diabetes patients with microalbumi- using clofibrate. Br Heart J 1978; 40: 1069–1118. nuria and dyslipidemia. Am J Nephrol 2001; 21: 56 Idzior-Walus B et al. Effects of comicronised fenofibrate 449–454. on lipid and insulin sensitivity in patients with 37 Diercks GF et al. Rationale, design, and baseline polymetabolic syndrome X. Eur J Clin Invest 2000; characteristics of a trial of prevention of cardiovascular 30: 871–878. and renal disease with fosinopril and pravastatin in 57 Morgan T et al. Simvastatin in the treatment of nonhypertensive, nonhypercholesterolemic subjects hypercholesterolemia in patients with essential hyper- with microalbuminuria (the Prevention of REnal tension. J Hypertens 1980; 8(Suppl 1): 525–530. and Vascular ENdstage Disease Intervention 58 Bradford RH et al. Expanded Clinical Evaluation of Trial [PREVEND IT]). Am J Cardiol 2000; 86: Lovastatin (EXCEL) study results. I. Efficacy in 635–638. modifying plasma lipoproteins and adverse event 38 Sundstrom J et al. Dyslipidemia and an unfavorable profile in 8245 patients with moderate hypercholester- fatty acid profile predict left ventricular olemia. Arch Intern Med 1991; 151: 43–49. hypertrophy 20 years later. Circulation 2001; 103: 59 Sung BH, Izzo Jr JL, Wilson MF. Effects of cholesterol 836–841. reduction on BP response to mental stress in patients

Journal of Human Hypertension Lipid lowering and blood pressure AS Wierzbicki

760 with high cholesterol. Am J Hypertens 1997; 10: cholesterol levels: results of AFCAPS/TexCAPS. Air 592–599. Force/Texas Coronary Atherosclerosis Prevention 60 Jarai Z et al. Effect of fluvastatin on serum lipid levels Study. JAMA 1998; 279: 1615–1622. in essential hypertension.] Orv Hetil 1996; 137: 1857– 72 Rubins HB et al. Gemfibrozil for the secondary 1859. prevention of coronary heart disease in men with low 61 Abetel G, Poget PN, Bonnabry JP. Hypotensive effect of levels of high-density lipoprotein cholesterol. Veterans an inhibitor of cholesterol synthesis (fluvastatin). A Affairs High-Density Lipoprotein Cholesterol Interven- pilot study]. Schweiz Med Wochenschr 1998; 128: 272– tion Trial Study Group. N Engl J Med 1999; 341: 277. 410–418. 62 Li N et al. Pravastatin affects blood pressure and 73 Haim M et al. Elevated serum triglyceride levels and vascular reactivity. Heart Vessels 1996; 11: 64–68. long-term mortality in patients with coronary heart 63 Murumatsu J, Kobayashi A, Hasegawa N, Yokouchi S. disease: the Bezafibrate Infarction Prevention (BIP) Hemodynamic changes associated with reduction in Registry. Circulation 1999; 100: 475–482. total cholesterol by treatment with the HMG-CoA 74 Byington RP et al. Reduction in cardiovascular events reductase inhibitor pravastatin. Atherosclerosis 1997; during pravastatin therapy. Pooled analysis of clinical 130: 179–182. events of the Pravastatin Atherosclerosis Intervention 64 Glorioso N et al. Effect of the HMG-CoA reductase Program. Circulation 1995; 92: 2419–2425. inhibitors on blood pressure in patients with essential 75 Sacks FM et al. Effect of pravastatin on coronary hypertension and primary hypercholesterolemia. disease events in subgroups defined by coronary risk Hypertension 1999; 34: 1281–1286. factors: the Prospective Pravastatin Pooling Project. 65 Staessen JA, Wang JG, Thijs L. Cardiovascular protec- Circulation 2000; 102: 1893–1900. tion and blood pressure reduction: a meta-analysis. 76 Sacks FM et al. The effect of pravastatin on coronary Lancet 2001; 358: 1305–1315. events after myocardial infarction in patients with 66 Staessen JA et al. Risks of untreated and treated average cholesterol levels. Cholesterol and Recurrent isolated systolic hypertension in the elderly: meta- Events Trial investigators. N Engl J Med 1996; 335: analysis of outcome trials. Lancet 2000; 355: 865–872. 1001–1009. 67 Randomised trial of cholesterol lowering in 4444 77 Sposito AC et al. Additional reduction in blood patients with coronary heart disease: the Scandinavian pressure after cholesterol-lowering treatment by statins Simvastatin Survival Study (4S). Lancet 1994; 344: (lovastatin or pravastatin) in hypercholesterolemic 1383–1389. patients using angiotensin-converting enzyme inhibi- 68 Pfeffer MA et al. Cholesterol and recurrent events: a tors (enalapril or lisinopril). Am J Cardiol 1999; 83: secondary prevention trial for normolipidemic pa- 1497–1499, A8. tients. CARE investigators. Am J Cardiol 1995; 76: 78 Davis BR et al. Rationale and design for the Anti- 98C–106C. hypertensive and Lipid Lowering Treatment to Prevent 69 Prevention of cardiovascular events and death with Heart Attack Trial (ALLHAT). ALLHAT Research pravastatin in patients with coronary heart disease and Group. Am J Hypertens 1996; 9: 342–360. a broad range of initial cholesterol levels. The Long- 79 Grimm Jr RH et al. Baseline Characteristics of Partici- Term Intervention with Pravastatin in Ischaemic pants in the Antihypertensive and Lipid Lowering Disease (LIPID) Study Group. N Engl J Med 1998; Treatment to Prevent Heart Attack Trial (ALLHAT). 339: 1349–1357. Hypertension 2001; 37: 19–27. 70 Shepherd J et al. Prevention of coronary heart disease 80 Sever PS et al. Rationale, design, methods and baseline with pravastatin in men with hypercholesterolemia. demography of participants of the Anglo-Scandinavian West of Scotland Coronary Prevention Study Group. N Cardiac Outcomes Trial. ASCOT investigators. J Hy- Engl J Med 1995; 333: 1301–1307. pertens 2001; 19: 1139–1147. 71 Downs JR et al. Primary prevention of acute coronary events with lovastatin in men and women with average

Journal of Human Hypertension