24-hour Ambulatory Blood Pressure - Relation to the - DiVA Portal

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KRISTINA BJÖRKLUND

Dissertation for the Degree of Doctor of Philosophy (Faculty of Medicine)in Geriatrics presented at Uppsala University in 2002

AbstractBjörklund, K. 2002. 24-hour Ambulatory Blood Pressure - Relation to theInsulin Resistance Syndrome and Cardiovascular Disease. Acta UniversitatisUpsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Facultyof Medicine 1199. 62 pp. Uppsala. ISBN 91-554-5451-8.

Hypertension constitutes part of the insulin resistance syndrome, and is a com-mon and powerful risk factor for cardiovascular disease in elderly. Blood pressure(BP) measured with 24-hour ambulatory monitoring gives however more de-tailed information and may be a better estimate of the true BP than conventionaloffice BP. This study examined relationships between 24-hour ambulatory BP and com-ponents of the insulin resistance syndrome, and investigated the prognostic sig-nificance of 24-hour BP for cardiovascular morbidity in a longitudinal popula-tion-based study of 70-year-old men. The findings indicated, that a reducednocturnal BP fall, nondipping, was a marker of increased risk primarily in sub-jects with diabetes. A low body mass index and a more favourable serum fattyacid composition at age 50 predicted the development of white-coat as opposedto sustained hypertension over 20 years. Furthermore, cross-sectionally deter-mined hypertensive organ damage at age 70 was detected in sustained hyperten-sive but not in white-coat hypertensive subjects. In a prospective analysis, 24-hour ambulatory pulse pressure and systolic BP variability at age 70 were strongpredictors of subsequent cardiovascular morbidity, independently of office BPand other established risk factors. Isolated ambulatory hypertension, defined ashaving a normal office BP but increased daytime ambulatory BP, was associatedwith a significantly increased incidence of cardiovascular events during follow-up. In summary, these data provide further knowledge of 24-hour ambulatory BPand associated metabolic risk profile, and suggest that the prognostic value of 24-hour ambulatory BP is superior to conventional BP in an elderly population.

Key words: hypertension, ambulatory blood pressure, insulin, fatty acids, progno-sis, morbidity

Kristina Björklund, Department of Public Health and Caring Sciences, Sectionof Geriatrics, Box 609, SE-751 25, Uppsala, Sweden

© Kristina Björklund 2002ISSN 0282-7476ISBN 91-554-5451-8Printed in Sweden by Uppsala University, Tryck & Medier, Uppsala 2002

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24-HOUR AMBULATORY BP

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KRISTINA BJÖRKLUND

Papers

This thesis is based on the following papers, which are referred to in thetext by their Roman numerals:

I. Björklund K, Lind L, Lithell H. Twenty-four hour blood pressure ina population of elderly men. J Internal Medicine. 2000; 248: 501-510.*

II. Björklund K, Lind L, Andrén B, Lithell H. The majority of nondip-ping men do not have increased cardiovascular risk: a population-basedstudy. Journal of Hypertension 2002;20:1501-1506.†

III. Björklund K, Lind L, Vessby B, Andrén B, Lithell H. Different meta-bolic predictors of white-coat and sustained hypertension over a 20-yearfollow-up period: a population-based study of elderly men. Circulation.2002;106:63-68.†

IV. Björklund K, Lind L, Zethelius B, Berglund L, Lithell H. Prognosticsignificance of 24-hour ambulatory blood pressure characteristics forcardiovascular morbidity in a population of elderly men. (In manuscript)

V. Björklund K, Lind L, Zethelius B, Andrén B, Lithell H. Isolatedambulatory hypertension predicts cardiovascular morbidity in elderlymen. (Submitted)

Reprints were made with permission from the publishers;* © Blackwell Science Ltd, and† © Lippincott Williams & Wilkins.

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Table of contents

Abbreviations.......................................................................6Introduction ........................................................................7

Hypertension in the elderly .................................................................... 8Hypertension and insulin resistance ...................................................... 10Circadian BP variation .......................................................................... 11

Aims of the study ..............................................................15Methods .............................................................................16

Subjects ............................................................................................. 16Investigations ..................................................................................... 19Definitions .......................................................................................... 23Statistical analyses ............................................................................... 24Discussion of Methods ......................................................................... 25

Results ...............................................................................28Paper I ............................................................................................... 28Paper II .............................................................................................. 29Paper III ............................................................................................ 31Paper IV ............................................................................................. 33Paper V .............................................................................................. 34

Discussion..........................................................................36Ambulatory BP normality - definition and consequences......................... 36Nondipping as cardiovascular risk indicator ........................................... 38White-coat hypertension and the insulin resistance syndrome ................. 39Prognostic value of 24-hour ambulatory BP ........................................... 42Predictive value of isolated ambulatory and white-coat hypertension ....... 44Clinical relevance ................................................................................ 47Strengths and limitations of the study ................................................... 49Future perspectives ............................................................................. 50

Conclusions .......................................................................52Acknowledgements ...........................................................53References .........................................................................55

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KRISTINA BJÖRKLUND

Abbreviations

ANOVA analysis of varianceACE angiotensin-converting enzymeBMI body mass indexBP blood pressureCE cholesterol esterCI confidence intervalCV coefficient of variationDBP diastolic blood pressureHDL high-density lipoproteinHR Cox proportional hazard ratioICD International Classification of DiseasesLDL low-density lipoproteinMAP mean arterial pressurePAI-1 plasminogen activator inhibitor-1PYAR person-years at riskSD standard deviationSBP systolic blood pressureUAER urinary albumin excretion rateULSAM Uppsala Longitudinal Study of Adult Men

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Introduction

Hypertension is a common and powerful risk factor for cardiovascular dis-ease.[1, 2] High blood pressure (BP) often co-exists with dyslipidemia, ab-dominal obesity and abnormal glucose metabolism,[3, 4] and such associat-ed metabolic risk factors further contribute to an adverse outcome in hyper-tension. In industrialised countries, the BP increases progressively with age,and it has been estimated that nearly 60% of the population in the USA atthe age of 70 have hypertension.[5] In the elderly, hypertension is common-ly characterised by an isolated increase in systolic BP (SBP), in contrast tothe predominantly elevated diastolic BP (DBP) component observed inyounger hypertensive subjects. Isolated systolic hypertension, for many yearsdisregarded by clinicians as a harmless physiological phenomenon, hasemerged as an important cardiovascular risk factor in elderly.[6] With anincreasing number of elderly people in our society, hypertensive disease andsubsequent organ damage constitute a major challenge for the health sectorin the nearest future.

The BP level in an individual is not constant, but continuously fluctuatesover time, depending on both internal and external factors. BP is most com-monly measured by a nurse or physician at the clinic. The clinic environ-ment may in some patients cause an alerting reaction and a sudden BP rise,the so-called “white-coat effect”, which can obscure the clinical judgement,and cause misclassification of the hypertensive status of the patient. Fur-ther, occasional measurements of conventional, or office BP, reflect the BPlevel at a limited time point of the day. Twenty-four-hour ambulatory BPmonitoring, on the other hand, eliminates the white-coat effect and pro-vides more comprehensive information about the “true” BP level duringboth day- and night-time. Previous findings have indicated that hyperten-sive target organ damage is closer related to mean 24-hour BP level thanoffice BP,[7, 8] and that the predictive value of 24-hour ambulatory BP forcardiovascular morbidity and mortality may be superior to office BP.[9-12]

The present study aimed to evaluate relationships between 24-hour am-bulatory BP and components of the insulin resistance syndrome, and fur-ther, to investigate the prognostic significance of 24-hour ambulatory BP forcardiovascular morbidity in a longitudinal population-based cohort of eld-erly men.

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KRISTINA BJÖRKLUND

Hypertension in the elderly

The ascendancy of systolic over diastolic BP - a paradigm shiftThe view on hypertension as a risk factor in the elderly has changed duringthe past 15-20 years. For many years, DBP was considered the most impor-tant measure of diagnosis and target for intervention, but recently, attentionhas focused more on the prognostic value of the SBP component, particular-ly in the elderly.[13, 14] An important factor that has influenced the newapproach to risk assessment in the elderly, is the emerging evidence fromobservational studies and clinical trials, showing that SBP, as risk indicator,is superior to DBP.

While the definition of hypertension until the beginning of the 1990’smainly took into account the DBP, new treatment recommendations in1993[15, 16] added SBP to the diagnostic criterion, since a number ofimportant clinical trials published around that time had reported highlybeneficial effects of antihypertensive treatment in elderly hypertensive pa-tients.[17-19] Hypertension in the elderly is typically characterised by anelevated SBP, but normal DBP, a hypertensive form which had previouslynot been comprised by the treatment guidelines. According to the mostrecent World Health Organization-International Society of Hypertension(WHO-ISH) guidelines from 1999, the upper limit of normal BP is consid-ered similar, 140/90 mmHg, for all age categories.[20]

Isolated systolic hypertension is the most common hypertensive subtypein elderly individuals,[21, 22] and constitutes a powerful predictor of cardi-ovascular disease.[6, 23-25] Furthermore, a wide pulse pressure has beenidentified as an independent risk factor for myocardial infarction,[26, 27]and may in fact be a stronger predictor of cardiovascular morbidity thanmean arterial pressure in elderly hypertensive subjects.[28, 29] During re-cent years, the results of a number of randomised controlled trials haveshown significant reductions of cardiovascular morbidity and mortality inelderly with isolated systolic hypertension.[18, 30, 31] Despite these docu-mented benefits of antihypertensive treatment, BP, and in particular SBP, ishowever still inadequately controlled in a large proportion of treated hyper-tensive patients.[32, 33]

Pathophysiological effects of aging on the vascular systemWith advancing age, there is a progressive increase in SBP while the level ofDBP plateaus, or even decreases,[5] resulting in a wider pulse pressure, i.e.difference between SBP and DBP. The age-related change in DBP may inpart result from early cardiovascular death in subjects with high DBP levels,but is in industrialized societies also reflected by structural changes of thelarge capacitance vessels due to arteriosclerosis. Simultaneously, the elasticproperties of the large arteries decrease, as the amount of elastin is reduced

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while the proportion of collagen in the arterial wall is increased. The conse-quence of these degenerative changes is thickening, hardening and dilata-tion of the aorta, carotids and other large elastic arteries, whereas the smallerperipheral arteries contain less elastin, and therefore are more durable.

The structural changes of the large arteries lead to a reduced distensibili-ty, and an increased velocity by which the pulse wave is transmitted fromthe left ventricle through the arterial tree, causing an early backward returnof the pulse wave from the periphery. This premature pulse-wave reflectioncauses an augmentation of the pressure during late systole, and a subsequentincrease in SBP and decrease in DBP.[34, 35]

Hypertensive target organ damageHypertensive disease has detrimental effects on structure and function ofthe vascular system and target organs. Hypertensive target organ damagemay be regarded as intermediate end-points, as opposed to cardiovascularmorbidity and mortality, termed “hard end-points”. The degree or presenceof left ventricular hypertrophy, carotid intima-media thickening, microalbu-minuria, increased serum creatinine and retinopathy, as measures of targetorgan damage, are important determinants of prognosis in hypertensive pa-tients.[20, 36, 37] On the other hand, regression of these parameters maybe used as markers for beneficial effect of antihypertensive treatment. Thedecision to treat a hypertensive patient should be based on evaluation of thetotal risk profile, including target organ damage and other prognostic factorssuch as smoking, diabetes, lipid profile and family history of cardiovasculardisease.[20]

Hypertension as a risk factor for cardiovascular diseaseThe major hazards of hypertension are the increased risk of coronary heartdisease and stroke. The associations between BP level and these outcomesare strong, continuous, and independent, although the DBP component isthe major risk determinant in younger populations,[2] and the SBP compo-nent in the elderly.[25] Thus, there does not seem to be an obvious thresh-old, below which the risk related to BP is negligible. The consequences ofthis apparently linear fashion of association between BP and cardiovascularrisk was recently illustrated by observational data from the FraminghamHeart Study, showing that a BP below the upper limits of normal, i.e. SBP130-139 and/or DBP 85-89 mmHg, is a predictor of cardiovascular disease,particularly in elderly individuals.[38]

A meta-analysis of previous intervention trials evaluating the effect ofantihypertensive drug therapy, has reported that by lowering DBP 5-6 mmHg,42% of strokes, but only 14% of coronary heart disease can be prevent-ed.[39] One of the reasons for the dissimilarity may be that the early clinicaltrials used solely an elevated DBP as inclusion criterion. This might have

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KRISTINA BJÖRKLUND

introduced a bias in the interpretation of the results, since subjects with lowDBP and high SBP, who are at high risk for coronary heart disease due to areduced coronary perfusion, were not included in those trials.[40] The “par-adox of coronary heart disease in hypertension” has also been attributed toother concomitant coronary risk factors, such as metabolic disturbances andincreased sympathetic activity, which may not be reduced by antihyperten-sive treatment, but continue to contribute to an adverse outcome despiteBP lowering.[41]

Hypertension and insulin resistanceThe clustering of hypertension with metabolic aberrations has been termedthe insulin resistance syndrome, or metabolic syndrome,[42, 43] and con-tributes to the increased risk of hypertensive target organ damage[44-46]and cardiovascular morbidity[47] in hypertension. There are several slightlydifferent working definitions of the insulin resistance syndrome,[48-50] ofwhich the most recent suggests that at least three of the following criteriashould be satisfied: Abdominal obesity, hypertriglyceridemia, low HDL-cholesterol level, hypertension and hyperglycemia.[50] It has recently beenreported,[51] that the prevalence of the insulin resistance syndrome, usingthe above definition, approximates 22% of the population in the UnitedStates, implying that metabolic abnormalities are highly prevalent, withimportant implications for cardiovascular health in the general population.

The etiology of hypertension is complex, and involves genetic as well asenvironmental factors. Among others, the interrelated factors obesity, hy-perinsulinemia and insulin resistance to glucose uptake, have been identi-fied as possible predictors of hypertension.[52, 53] Increased sympatheticnervous activity, which is particularly evident in the early phases of hyper-tension development, has been proposed as a possible common link be-tween many of the metabolic abnormalities characteristic of the insulinresistance syndrome.[41] Moreover, dietary factors are associated with BP,[54]and the quantity as well as the quality of the dietary fat seems to be ofimportance. The dietary fat quality has previously been related to insulinsensitivity[55] and shown to predict the development of type 2 diabetes[56]in the presently studied ULSAM population. The Dietary Approaches toStop Hypertension (DASH) Trial, showed that a combination diet rich infruits and vegetables, and low in total and saturated fat had a significant BP-lowering effect during 24 hours.[57] However, the possible long-term longi-tudinal relationship between dietary fat intake and hypertension still re-mains to be elucidated.

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Circadian BP variationWhen biological systems exhibit prominent and reproducible patterns oc-curring regularly over a 24-hour period, they are referred to as circadian.During recent years, there has been an increasing interest in the circadianBP variability, and its impact on cardiovascular risk. The occurrence of con-tinuous fluctuations in BP was first described by Stephen Hales in 1733,who measured BP by inserting a brass tube into the carotid artery of a horse.He concluded from these pioneering experiments, that BP was “never to beexactly the same, any two minutes, throughout the whole life of an ani-mal”.[58]

It is now known that a number of factors involved in atherothromboticformation; hemodynamical, neural, hormonal and hematological, undergoa regular variation during day and night. The incidence of cardiovascularevents such as myocardial infarction,[59] stroke[60] and sudden cardiacdeath[61] also display a circadian rhythm, with a peak incidence in themorning when BP, heart rate and platelet aggregation are increased andfibrinolysis is low. Therefore, it has been suggested that these dynamical,physiological mechanisms may contribute to, or maybe even trigger, theonset of acute cardiovascular events.

Fluctuations in BP are influenced by external factors in daily life (Table1) as well as by an internal biological rhythm. Plasma cortisol reaches a peak

Effect on blood pressure (mmHg)

Table 1. Effect of different daily activities on BP level. The changes shown are relativeto BP while relaxing. (Adapted from Campbell )

Activity Systolic BP Diastolic BPAttending a meeting + 20 + 15Walking + 12 + 6Talking on telephone + 10 + 7Reading + 2 + 2

at the time of awakening,[62] with subsequent increases in plasma catecho-lamines during the late morning hours. The a-sympathetic vasoconstrictoractivity shows a circadian variation, with an increased vascular tone in themorning which may contribute to the increased BP observed at this time.[63]Furthermore, autonomic cardiovascular mechanisms, in particular the arte-rial baroreflexes, are important determinants of the degree of BP variabili-ty.[64]

Variability of BP can be assessed over shorter or longer time-periods, andmay be described as morning BP rise, night-day BP difference, or as thestandard deviation of the average BPs obtained during the day or night. An

[190]

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KRISTINA BJÖRKLUND

increased BP variability over 24 hours is cross-sectionally associated withtarget organ damage in hypertensive patients[65, 66] and in the generalpopulation,[67] and also seems to carry prognostic information for the de-velopment of target organ damage.[68, 69] Longitudinal findings, althoughcurrently sparse, further suggest that BP variability may predict cardiovascu-lar mortality, independently of BP level.[70]

Twenty-four-hour ambulatory BP monitoringBP is commonly measured in the clinic, and repeated clinic, or office BPs,are used as a basis for treatment decisions and evaluation of BP control.However, office BP monitoring has several limitations. Potential problemsthat may affect the accuracy of the measurement include observer bias suchas terminal digit preference and measurement error. There is also a possibil-ity that BP measured at the office is not representative of the “true” BP indaily life, and that some subjects experience an excessive emotional responseto the clinic environment, termed “white-coat hypertension”.

Twenty-four hour ambulatory BP monitoring, on the other hand, offers areading devoid of the white-coat effect, and more accurately reflects theactual 24-hour BP load imposed on the vascular bed. In addition, ambula-tory BP monitoring provides valuable information beyond that obtainedwith conventional BP readings, since entities such as BP variability and night-time BP level, which seem to have prognostic significance, can only be meas-ured with 24-hour ambulatory monitoring.

Reference values of normal 24-hour BP have recently been proposed,[71]and ambulatory BP monitoring is still used to a limited extent in clinicalpractice. According to current guidelines, ambulatory BP monitoring is es-pecially indicated in certain subgroups, such as patients with borderlinehypertension, pregnant women, patients with treatment-resistant hyperten-sion, in patients with symptoms suggesting episodes of hypotension and inelderly individuals.[20, 72]

There are several reasons why the elderly may benefit from ambulatoryBP monitoring. Elderly subjects more often than younger display an in-creased BP variability, which might obscure office BP readings. In addition,elderly have a higher prevalence of hypotensive states due to autonomicdysfunction, and the symptoms may worsen by a high susceptibility to theadverse effects of antihypertensive drugs. Misclassification of hypertensionleading to unnecessary medication is therefore particularly harmful in olderpatients.

Closer relationships have previously been found between hypertensivetarget organ damage and ambulatory BP than office BP,[7, 8] and prospec-tive studies have indicated that 24-hour ambulatory BP is an independentpredictor of cardiovascular disease,[9-12] as shown in Table 2. Information

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regarding the prognostic role of 24-hour ambulatory BP in elderly subjectsfrom the general population, is however limited.

ydutS noitalupopydutSnaeM

pu-wollof)sraey(

tniop-dnE )IC%59(oitarksiR

obukhO ,noitalupoplareneg,2451=nsry26~eganaem 1.5 ralucsavoidraC

ytilatrom†)670.1-810.1(740.1

)PBSgHmm1/(

nodeR ,noisnetrepyhyrotcarfer,68=nsry35eganaem 1.4 ralucsavoidraC

ytidibrom†)1.82-83.1(02.6

)PBDelitrettsrifsvdriht(

aihccedreV ,noisnetrepyh,0102=nsry25eganaem 8.3 ralucsavoidraC

ytidibrom†)53.1-21.1(32.1

)PBSgHmm01/(

rattahK ,noisnetrepyh,886=nsry15eganaem 2.9 ralucsavoidraC

ytidibrom)32.1-60.1(41.1)PBSgHmm01/(

nesseatS cilotsysdetalosi,808=nsry07eganaem,noisnetrepyh

4.4)naidem(

ralucsavoidraCytidibrom

†)53.1-10.1(71.1)PBSgHmm01/(

Table 2. Previous longitudinal studies investigating prognostic value of ambulatory BP.

† indicates that the risk is independent of office BP level

[11]

[12]

[166]

[167]

[191]

NondippingThe BP normally decreases during night-time. A reduced nocturnal BP re-duction, or nondipping BP pattern, was first reported in conditions such asautonomic failure[73] and diabetes,[74] but nocturnal BP fall has later beenshown to be normally distributed in the general population.[75] A bluntedreduction of nocturnal BP has been associated with increased left ventricu-lar mass,[66] cerebrovascular disease,[76] and renal dysfunction.[77] How-ever, due to the cross-sectional design of these studies, it can not be con-cluded whether the organ damage is a cause or effect of the disturbed night-day BP pattern. Furthermore, other investigators have reported that nondip-pers and dippers do not differ regarding hypertensive target organ dam-age,[78, 79] suggesting that the clinical implication of the nondipping phe-nomenon needs further clarification.

Several previous studies investigating the cardiovascular risk associatedwith nondipping have been performed in selected populations of hyperten-sive subjects, and some have not adjusted for diabetes in their analyses. Thequestion therefore persists whether nondipping is a marker of risk, inde-pendently of diabetes, in a population setting.

White-coat hypertension and Isolated ambulatory hypertensionAs illustrated in Figure 1, four different states are possible to identify ac-cording to office and ambulatory BP monitoring: first, normotension at bothrecordings; second, white-coat hypertension, when office BP is elevated but

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KRISTINA BJÖRKLUND

daytime ambulatory BP is normal; third, isolated ambulatory hyperten-sion, when office BP is normal but ambulatory daytime BP elevated; andfourth, sustained hypertension, defined as an elevation of both office andambulatory daytime BP.

White-coat hypertension is a condition characterized by a persistentlyraised office BP in combination with a normal daytime ambulatory BP.[72]The white-coat effect, on the other hand, is defined as a transient rise inBP from before to during the visit at the clinic,[80] most reliably measured

Fig 1. Subgroups possible to identifyaccording to office and ambulatoryBP measurement.

with a continuous beat-to-beat BP monitoring technique. When there is adiscrepancy between office and ambulatory pressure, as in white-coat hy-pertension, the prognosis has been suggested to be more closely related toambulatory BP.[81] However, the clinical relevance of white-coat hyperten-sion is still being disputed.

An association between white-coat hypertension and hypertensive targetorgan damage has been indicated by some previous investigators,[82-84]although this could not be supported by others.[85, 86] Furthermore, anincreased resting heart rate and metabolic aberrations have been observed tobe similar in white-coat and sustained borderline hypertensives, implyingthat white-coat hypertension is not an entirely innocent phenomenon.[87]Prognostic data suggest that white-coat hypertension may not be associatedwith a higher cardiovascular morbidity than normotension,[88, 89] but ad-ditional studies are required to confirm those findings. Moreover, by gaininginformation about predictors of white-coat hypertension we may increasethe understanding of the mechanisms behind this condition, as opposed tosustained hypertension.

White-coat hypertension has been quite extensively studied over the pastyears. However, little is known about the prevalence and prognostic role ofthe converse phenomenon, isolated ambulatory hypertension, characterizedby an increased BP during daytime but normal office BP. Recently, cross-sectional data indicated that isolated ambulatory hypertension may be asso-ciated with metabolic risk factors and target organ abnormalities to a similarextent as sustained hypertension, a state with elevated office and ambulatoryBP.[90, 91] The prognostic significance of this condition is thus far unknown.

Office BP

Ambu

lato

ryBP

Normal

Isolated ambulatory

hypertension

White-coathypertension

Sustainedhypertension

Office BP

Ambu

lato

ryBP

Normal

Isolated ambulatory

hypertension

White-coathypertension

Sustainedhypertension

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Aims of the study

I. To describe ambulatory and office BP characteristics and establish refer-ence values of normal ambulatory BP in a longitudinal population-basedstudy of 70-year-old men, and further, to evaluate the prevalence of hyper-tension and BP control in treated elderly hypertensive subjects in this popu-lation.

II. To cross-sectionally evaluate whether nondipping and diabetes are inde-pendently related to components of the insulin resistance syndrome andprevalence of hypertensive target organ damage, using metabolic and echocar-diographically determined variables measured in 70-year-old men.

III. To examine whether metabolic status and biomarkers of dietary fatquality measured in men at age 50 may predict the development of sus-tained and white-coat hypertension over the following 20-year-period, andfurther, to cross-sectionally compare subjects with sustained and white-coathypertension at age 70 regarding metabolic risk factors and hypertensivetarget organ damage.

IV. To investigate the prognostic significance of 24-hour ambulatory BPand BP variability for cardiovascular morbidity in 70-year-old men from thegeneral population, over a mean follow-up of 6.6 years.

V. To cross-sectionally examine the metabolic and cardiac risk profile in,and investigate the prognostic value of isolated ambulatory hypertension forcardiovascular morbidity in 70 year-old men.

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KRISTINA BJÖRKLUND

Methods

Subjects

ULSAMThe papers in this thesis are based on a cohort of men born in 1920-24, theUppsala Longitudinal Study of Adult Men (ULSAM). This cohort originat-ed in 1970-73, when all 50-year-old men living in the municipality ofUppsala were invited to participate in a health examination, which aimedto detect risk factors for cardiovascular disease and identify high-risk indi-viduals for intervention.[92] Of the 2841 subjects invited, 2322 men par-ticipated in the investigation at age 50 years (participation rate 82%). There-after, the participants have been invited to three re-investigations, at theapproximate ages of 60, 70 and 77. In this thesis, data are used from theinvestigations at age 50 and 70 years (Figure 2). Between the baseline inves-tigation in the 1970s and 1991, 422 subjects had died and 219 had movedout of the Uppsala region. In 1991-95, 1221 of the 1681 men who were

Age 50 Age 70

2841invited

2322participants

422 died

219 moved

1681invited

1221participants

217 died(2000-12-31)

1970-73 1991-95

Age 50 Age 70

2841invited

2322participants

422 died

219 moved

1681invited

1221participants

217 died(2000-12-31)

1970-73 1991-95

Figure 2. The ULSAM population.

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alive and still living in Uppsala, took part in the re-investigation (participa-tion rate 73%). At this re-investigation at age 70 years, a 24-hour ambulato-ry BP monitoring was performed. The study was approved by the EthicsCommittee of Uppsala University, and all participants gave written informedconsent. All investigations were done after an overnight fast. A reproducibil-ity study was performed in 22 subjects approximately 1 month after theexamination at age 70 years, from which the intra-individual coefficients ofvariation (CVs) are presented.

Study PopulationsA schematic description of the study populations is provided in Figure 3.

Paper I. The study population in Paper I consisted of the 1060 70-year-old-men with technically satisfactory recordings from the ambulatory BPmonitoring, and non-missing information regarding antihypertensive treat-ment at the investigation at age 70 years.

Paper II. Of the 1060 70-year-old subjects who constituted study popu-lation in Paper I, 1057 men with information on anti-diabetic treatmentwere also included in Paper II. These 1057 men were the basis for the studypopulations in Paper III-V. Measures of hypertensive target organ damage,represented by urinary albumin excretion rate (UAER) and echocardiographicdata, were analysed in those subgroups of men with available informationon these respective variables.

Paper III. From the 1057 70-year-old men defined in Paper II, 373 sub-jects with antihypertensive treatment were excluded, as were also 82 sub-jects with elevated ambulatory but normal office BP, leaving 602 men forthe analysis. In Paper III, two separate analyses were performed, one cross-sectional at age 70 years, and one longitudinal, where data from the investi-gation at age 50 years were examined in subjects who had been divided insubgroups on the basis of BP readings at age 70 years. In the cross-sectionalanalysis, data regarding urinary albumin excretion rate (UAER) and echocar-diographic measures, were analysed in subgroups of men with available in-formation on these respective variables.

Paper IV. Men from the investigation at age 70 years, who fulfilled theinclusion criteria for Paper II (n=1057), and who had non-missing informa-tion regarding smoking habits were included in Paper IV. Moreover, subjectswho had previously been hospitalized due to coronary heart disease (Inter-national Classification of Diseases (ICD) -9 codes 410-414; n=125) andcerebrovascular disease (ICD-9 codes 431-436; n=42) were excluded. Theremaining 872 subjects formed study population in Paper IV.

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KRISTINA BJÖRKLUND

Figure 3. Description of study populations in Papers I-V. BP, blood pressure; UAER, urinaryalbumin excretion rate.

III

Age 70 years

1057 602Age 50 years

373+82excluded

584

288with echo-cardiography

with UAER

602

I 1221 1060

Age 70 years 108 missing data office or ambulatory BP

53 missing data antihypertensive treatment

II

Age 70 years

1060 1057

3 missing data antidiabetic treatment

1017


with UAER

IV

V

Age 70 years

1057167excluded

87218 missing data smoking habits

578

Age 70 years

1057

373+106excluded

512

60 excluded



III

Age 70 years


373+82excluded

584


with UAER

602

III

Age 70 years


373+82excluded

584


with UAER

602

I 1221 1060



1221 1060



II

Age 70 years

1060 1057


1017


with UAER

Age 70 years

1060 1057


1017


with UAER

IV

V

Age 70 years

1057167excluded


Age 70 years

1057167excluded


Age 70 years

1057167excluded


578

Age 70 years

1057

373+106excluded

512

60 excluded



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Paper V. The 1057 men with satisfactory information regarding ambula-tory BP and treatment for hypertension and diabetes at the investigation atage 70 years, constituted the basis for Paper V. We excluded 373 subjectswho were taking antihypertensive medication, as well as 106 individualswith normal daytime ambulatory, but elevated office BP, leaving 578 mento constitute study population. Prior to the investigation at age 70 years, 40subjects had been hospitalized due to coronary heart disease (ICD-9 codes410-414) and 20 due to stroke (ICD-9 codes 431-436), and these 60 sub-jects were excluded from the survival analysis, as well as 6 subjects withmissing information on smoking habits.

Antihypertensive treatmentOf all 2322 50-year-old men who participated in the investigation in 1970-73, 98 subjects were treated with antihypertensive agents. In the presentthesis, data from the investigation at age 50 were used in 602 men (PaperIII), and these 602 subjects were free from antihypertensive treatment atage 50 years. At the investigation at age 70 years, 285 (27%) of the 1060men with technically satisfactory ambulatory BP recordings (Paper I) wereunder regular treatment with antihypertensive medication, whereas 9% weretaking drugs with antihypertensive properties for other reasons than hyper-tension (post-myocardial infarction, angina etc).

Of the 285 70-year-old men with treated hypertension, 155 were onmonotherapy, 104 had two antihypertensive drugs and 26 had three or moredrugs. The most frequently used antihypertensive drug was a beta-blocker,used by 162 subjects, whereas a calcium antagonist was used by 110 sub-jects, diuretics by 103 subjects, ACE-inhibitors by 55 subjects and alpha-blockers by 13 subjects.

Investigations

Measurements at age 50 yearsAnthropometry. Height (without shoes) was measured to the nearest wholecm and weight (in undershorts) to the nearest whole kg. Body mass index(BMI) was calculated as weight (in kg) divided by height (in meters) squared.

Office BP. BP in the right arm was measured after 10 minutes’ rest in therecumbent position, using a mercury manometer (Kifa Ercameter, wall-mod-el). The BP cuff was 12.5 cm wide and 35 cm long. SBP and DBP were readto the nearest 5 mmHg mark. The radial pulse rate was counted after 10minutes’ rest before the BP measurement.

20

KRISTINA BJÖRKLUND

Glucose and insulin. Whole blood glucose concentration was measured byusing the glucose oxidase method. An intravenous glucose tolerance test wasperformed by injection of a 50% solution of glucose at a dose of 0.5 g/kgbody weight into an antecubital vein during 2.5 minutes. Blood glucoseconcentrations were determined before and 6, 20, 30, 40, 50 and 60 min-utes after the start of the glucose injection, and the levels between 20 and60 minutes were used for calculation of glucose tolerance. This was ex-pressed as the K-value calculated from the formula: K=ln2·100/T1/2 whereT1/2 is the time in minutes required for the concentration to be reduced byhalf its value. Specific insulin concentrations were determined using theAccess Immunoassay System (Beckman-Coulter), which uses a chemilumi-nescent immunoenzymatic assay. These analyses were carried out between1995 and 1998 in Cambridge, UK, using plasma samples that had beenstored frozen (in -70°C) since sampling in 1970-73.

Serum lipids. Determinations of serum cholesterol and triglyceride concen-trations were performed on a Technicon Auto Analyzer type II[93] in 1981-82 on serum samples that had been stored in liquid nitrogen since 1970-73.HDL cholesterol was assayed in the supernatant after precipitation with aheparin/manganese-chloride solution. LDL cholesterol was calculated usingFriedewald’s formula: LDL=serum cholesterol-HDL-(0.42·serum triglycer-ides). The fatty acid composition in serum cholesterol esters (CE) was deter-mined using gas-liquid chromatography, as previously described in detail.[56]The CE fatty acids are presented as the relative percentage of the sum of thefatty acids analysed.

Questionnaire. Data regarding medical treatment and heredity for hyper-tension were collected through a self-administered questionnaire. Informa-tion on smoking habits (smoking, non-smoking) was retrieved through aninterview by a physician.

Measurements at age 70 yearsAnthropometry. Height was measured to the nearest whole cm, and bodyweight to the nearest 0.1 kg. The waist and hip circumferences were meas-ured in the supine position, midway between the lowest rib and the iliaccrest and over the widest part of the hip, respectively. The waist/hip ratiowas calculated.

Office BP. Office BP was measured in the right arm with a sphygmomanom-eter. The cuff size was 12.35 cm or 15.45 cm depending on the arm cir-cumference. The recordings were made to the nearest 2 mmHg twice after10 minutes supine rest, and the mean of the two measurements were usedfor the analyses. SBP and DBP were defined as Korotkoff´s phases I and V,

21


respectively. Mean arterial pressure (MAP ) was calculated according to theformula MAP = DBP + 1/3 (SBP - DBP). We estimated pulse pressure asthe difference between SBP and DBP. The resting heart rate was measuredas supine pulse rate during one minute. The CVs for office SBP and DBPwere 7.2% and 4.9% respectively.

Ambulatory BP. Ambulatory BP was recorded using the Accutracker 2 equip-ment (Suntech Medical Instruments Inc, Raleigh NC, USA). The devicewas attached to the subject´s non-dominant arm by a skilled lab technician,and BP was measured during 24 hours starting at 11 a.m. BP recordingswere made every 20th minute during the whole 24-hour period. Prior toNovember 1993, BP was measured every 30th minute during daytime (06.00-23.00) and every hour during night-time (23.00-06.00). Data were editedby omitting all readings of zero, all heart rate readings <30, DBP readings>170 mmHg, SBP readings >270 and <80 mmHg, and all readings wherethe difference between SBP and DBP was less than 10 mmHg. Subjectswith ≥4/10 hours of recorded and technically satisfactory BP during day-time, and respectively, ≥3/6 hours of recorded BP during night-time, wereincluded in the study. SBP and DBP were given by the auscultatory device.Mean arterial pressure was calculated according to the formula MAP =DBP + 1/3 (SBP - DBP). We estimated pulse pressure as the differencebetween SBP and DBP. BP variability was defined as the standard deviation(SD) of the hourly mean BP values during daytime and night-time for SBPand DBP respectively. The CVs for 24-hour SBP and DBP were 6.8% and5.5% respectively.

Glucose and Insulin. Plasma glucose was measured by the glucose dehydro-genase method (Gluc-DH, Merck). An oral glucose tolerance test was per-formed where the subjects ingested 75 g glucose dissolved in 300 ml ofwater, and blood samples for plasma glucose and insulin were drawn imme-diately before, and 30, 60, 90, and 120 min after ingestion of glucose.Plasma insulin was assayed using an enzymatic-immunological assay (En-zymmun, Boehringer Mannheim) performed in an ES300 automatic analys-er (Boehringer Mannheim). Intact proinsulin and 32-33 split proinsulinconcentrations were analysed using the two-site immunometric assay tech-nique.[94] Specific insulin concentrations were determined using the Ac-cess Immunoassay System (Beckman-Coulter).

Insulin sensitivity was assessed by using the euglycaemic hyperinsulinae-mic clamp technique according to DeFronzo et al, but slightly modified,whereby insulin (Actrapid Human(r), Novo) was infused at a rate of 56(instead of 40[95]) mU/min per body surface area (m2). Glucose uptake(M) was calculated as the amount of glucose (milligrams) infused per minuteper body weight (kilograms). The insulin sensitivity index (M/I) was calcu-lated by dividing M by the mean insulin concentration during the same

22

KRISTINA BJÖRKLUND

period of the clamp and represents the amount of glucose metabolised perunit of plasma insulin (mg×min-1×kg-1/(100mU/L)).

Serum lipids. Cholesterol and triglyceride concentrations in serum were as-sayed by enzymatic techniques (Instrumentation Laboratories) in a Mon-arch 2000 centrifugal analyser. HDL particles were separated by precipita-tion with magnesium chloride/phosphotungstate. LDL cholesterol was cal-culated using Friedewald’s formula (above). Nonesterified fatty acids weremeasured by an enzymatic colorimetric method (Wako Chemical GmbH).

PAI-1-activity. Plasminogen activator inhibitor-1 (PAI-1) activity was ana-lysed with a commercial two-step indirect enzymatic assay (Spectrolyse/pLPAI, Biopool AB) as described previously.[96, 97]

Echocardiography. M-mode, two-dimensional and Doppler echocardiograph-ic examinations were performed in the first 583 consecutive subjects in theoriginal study population at age 70,[98] leaving 488 (Paper II), 288 (PaperIII) and 234 (Paper IV) subjects with echocardiographic data in the respec-tive Papers of the present thesis. Left ventricular mass was determined byusing the M-mode formula of Troy according to the recommendations ofthe American Society of Echocardiography,[99] and was further divided bybody surface area to obtain left ventricular mass index. Relative wall thick-ness was calculated as (Intraventricular septal thickness + posterior wall thick-ness/left ventricular end diastolic diameter). The CVs were 12.5% and 6.9%for left ventricular mass index and relative wall thickness respectively.

Urinary albumin excretion. Albumin was measured in urine (AlbuminRIA100, Pharmacia, Sweden) and the urinary albumin excretion rate (UAER)was calculated on the amount of urine collected during the night togetherwith the first sample of urine after rising. Microalbuminuria was defined asa UAER of 20-200µg/min.

Questionnaire. Data concerning ongoing medical treatment were collectedwith a self-administered questionnaire. Leisure time physical activity wasassessed using the four questions: 1) Do you spend most of your time read-ing, watching TV, going to the cinema or engaging in other, mostly seden-tary activities?, 2) Do you often go walking or cycling for pleasure?, 3) Doyou engage in any active sport or heavy gardening for at least 3 hours everyweek?, 4) Do you regularly engage in hard physical training or competitivesport? Based on these questions, four physical activity categories were con-structed: Sedentary, Moderate, Regular and Athletic. Information on smok-ing habits (smoking, non-smoking) was retrieved through interview reports.

A dietary assessment was performed using a 7-day precoded food record;prepared and validated by the National Food Administration (NFA).[100]

23


Follow-upThe cohort was followed for up to 9.5 years (Paper IV) since the investiga-tion at age 70, with a mean follow-up period of 6.6±2.1 years. Outcomeevents were assessed using data from the Swedish Hospital Discharge andCause of Death Registries (censor dates December 31, 1999 (Paper V) andDecember 31, 2000 (Paper IV) respectively).

Cardiovascular morbidity was defined as a composite end-point, includ-ing death from coronary heart disease (ICD-9 codes 410-414, or ICD-10codes I20-I25) and stroke (ICD-9 codes 431-436, or ICD-10 codes I61-I66), as well as first hospitalisation for non-fatal coronary heart disease andstroke (Paper IV). In Paper V, we also included death from peripheral vascu-lar disease (ICD-9 codes 440-444, or ICD-10 codes I70-I74) in the com-posite end-point. During 9.5 years of follow-up, contributing to 5784 per-son-years at risk (PYAR), a total of 172/872 cardiovascular events (2.97/100 PYAR) occurred, including 115 coronary events, of which 27 werefatal, and 57 strokes, of which 7 were fatal. Cardiovascular morbidity, de-fined by combining data from the Hospital Discharge and Cause of DeathRegistries, is an efficient, validated alternative to revised hospital dischargenotes and death certificates.[101, 102]

DefinitionsIn Papers I and II, hypertension was defined as either taking regular antihy-pertensive treatment, or having an office SBP ≥140 and/or DBP ≥90 mmHg,according to the guidelines of JNC VI[103] and WHO-ISH[20]. For the24-hour ambulatory BPs, we used short fixed-clocktime intervals and de-fined daytime as 10 a.m. to 8 p.m. and nighttime as midnight to 6 a.m.[75,104] Besides the diary method, considered most reliable, fixed-time meth-ods where the morning and evening phases are excluded increases the accu-racy in estimating the actual sleep and awake periods.[105] An elevateddaytime ambulatory BP was defined as ≥135/85 mmHg.[72, 103] In PaperIII, where all subjects were untreated, we distinguished between white-coathypertension, defined as office BP ≥140/90 and daytime BP <135/85 mmHg,and sustained hypertension, defined as office BP ≥140/90 and daytime BP≥135/85 mmHg. Subjects with normal office BP (<140/90 mmHg) anddaytime ambulatory BP ≥135/85 mmHg were entitled isolated ambulatoryhypertensive in Paper V.

The ratio between night SBP and day SBP was used to define the dippingstatus (Paper II). A night-day SBP ratio of ≥1.0 was considered nondipping,whereas a ratio of <0.8 was regarded extreme dipping. Dipping was definedas a night-day SBP ratio <1.0, except for in a separate analysis of extremedipping, where dippers were subdivided into extreme dippers (defined above)

24

KRISTINA BJÖRKLUND

and moderate dippers (>0.8 - <1.0). In Paper I, the night-day ratio wasmultiplied by 100, expressing nighttime BP as a percentage of the daytimelevel.

Diabetes (Paper II-V) and impaired glucose tolerance (Paper II) at age 70years were defined according to the 1985 WHO criteria.[106] A serumcholesterol level >6.5 mmol/L and/or use of lipid-lowering medications wascharacterized as hyperlipidemia (Paper IV).

Statistical analysesThe statistical software packages Stata 6.0 (Stata Corporation; Papers I-V),JMP and SAS 8.2 (SAS Institute, Cary, NC; Papers I and IV respectively)were used for the analyses. Distributions were tested for normality by Sha-piro-Wilk´s W test, and when skewed, variables were logarithmically trans-formed to reach normal distribution. Two-tailed significance values weregiven with p<0.05 regarded as significant. We used ANOVA to calculatedifferences in means, and comparisons between subgroups were carried outif the overall F-test was significant. Bonferroni correction was performed inpost-hoc analyses of more than two groups.

In Paper I, the correspondence between clinic and ambulatory BP wasanalysed by linear regression analysis. In Paper II, a number of metabolicvariables and variables indicating target organ damage were considered out-come variables. For each outcome variable the relation to nondipping anddiabetes were estimated from a model in which these factors and their inter-action were analysed. For outcome variables where the interaction term wasnon-significant a limited model was used, excluding this term. Proportionaldifferences between the groups were calculated by the chi-square test. Theimpact of potential confounders was taken into account by using analysis ofcovariance (Papers II-III).

Cox Proportional Hazard Regression was used to calculate crude andmultivariate-adjusted hazard ratios of cardiovascular morbidity and their95% confidence intervals (CI) over the time of follow-up since the investi-gation at age 70 years (Papers IV-V). In Paper IV, longitudinal relationshipsbetween BP and cardiovascular morbidity were assessed using standardizedcontinuous BP variables, so that the hazard ratio from the Cox Regressionreflected the predictive value of a 1 SD increase in a BP component. Inmultivariate Cox models, adjustment was made for potential confounders,treating categorical variables as dichotomous (1/0), and continuous varia-bles as standardized variables (Papers IV-V). In Paper V, the hazard ratiorepresented the risk associated with the hypertensive categories defined atage 70 years. To test the significance of the additional prognostic informa-tion obtained by 24-hour pulse pressure in Paper IV, likelihood ratio tests

25


were performed between pairs of maximum likelihood models, giving a χ2

statistic which was twice the difference between the log-likelihoods be-tween models including and excluding 24-hour pulse pressure. To test thenull hypothesis of equal hazard ratios for two BP variables in different mod-els, in which a set of other variables were the same, we used a bootstrapmethod (Paper IV). The bootstrap method was based on 10 000 replicatedsamples.[107]

Discussion of Methods

Methodology of BP measurementsIt is known that the BP in clinical studies tends to be higher at the first visitcompared with later visits. According to international standards, a diagnosisof hypertension should be based on repeated BP measurements at separateclinic visits, the number of office measurements being dependent on the BPlevel and the overall cardiovascular risk profile.[108] Office BP in the UL-SAM cohort, like in many population studies, was the mean of two readingsat a single visit, a simplified screening procedure which may have inducedmeasurement error, and possibly overrated the number of subjects classifiedas hypertensive according to office BP. Office BP was measured in the su-pine position both when the subjects were 50 and 70 years, in agreementwith Swedish clinical practice. Supine measurements tend to cause slightlylower DBP than when BP is measured sitting, however this difference de-creases with age.[109]

At the investigation at age 50 years, the office BP was either taken by oneregistered nurse, or by one physician (Hans Hedstrand). The mean BP ob-tained by the physician in 231 subjects was 131.5/83.0 mmHg. The corre-sponding BP obtained by the nurse in 216 men was 131.8/83.7 mmHg,suggesting that the systematic error induced by different observers was verysmall.[110]

In the 70-year-old men, office BP was measured by a nurse in all subjects.The ambulatory BP recordings were performed by a skilled lab technician.Subjects were asked to try to hold the arm still when the cuff was inflated,to facilitate the recording. The BP measurement procedure changed duringthe time of investigation, in that BP during night-time was measured onceevery hour between August 1991 and October 1993, and once every 20minutes between November 1993 and May 1995. This increased frequencyof readings may have increased the precision of the mean BP calculatedfrom all intermittent readings in the subjects investigated during the latterpart of the investigation period. Compared with intra-arterial continuousambulatory BP recordings, which is considered the golden standard method

26

KRISTINA BJÖRKLUND

of 24-hour BP measurement, the now widely used non-invasive techniquesof intermittent BP recordings provide accurate assessment of true averageBP.[111]

The Accutracker II device has recently been validated against protocolsfrom the British Hypertension Society (BHS) and the American Associationfor the Advancement of Medical Instruments (AAMI).[112] Accutracker IIfulfilled the AAMI protocol, but failed to pass the BHS protocol due to aninsufficient agreement with mercury standard regarding DBP.[113] Howev-er, the Accutracker II device showed satisfactory accuracy and precision ac-cording to available documentation at the time of investigation in the be-ginning of the 1990´s.[114, 115] In the present study, the reproducibilityof ambulatory BP was high, in agreement with previous investigations ofelderly subjects.[116]

Dichotomization of a continuous variable - classification ofsubgroupsTwenty-four hour ambulatory BP monitoring has made it possible to identi-fy subjects with elevated night-time BP, blunted nocturnal BP reduction,increased BP variability and discrepancies between office and daytime BPelevation. BP data can be presented and analysed as either continuous orcategorical variables. The use of continuous variables may be preferable,since this approach takes into account the fact that BP is related to cardio-vascular disease risk in an approximately linear fashion,[2] meaning that therisk starts to increase with an increase in BP even at levels below the cut-offfor what is regarded as hypertension.[38]

However, clinicians need guidance by limits of normal BP in order tomake decisions regarding diagnosis and treatment. The term hypertensionas well as the concepts of white-coat hypertension, isolated ambulatory hy-pertension and nondipping, inevitably implies a classification of subjectsinto subgroups on the basis of cut-off limits of ambulatory and office BP.This assumes an arbitrary dichotomization of continuous variables, and un-til reference values have been agreed upon, caution should be taken regard-ing various definitions of the phenomena. Risk assessment of white-coathypertension and nondipping will be highly dependent on the definitionused.

Selection biasThe 161 subjects who were excluded from the initial 1221 subjects investi-gated at age 70 (Paper I), were evenly distributed across the birth-span 1921-24, with the exception of a slightly larger amount of the men born in 1920being excluded. Since during the first 2 years of the investigation, night-time BP was measured but once every hour, and the men born in 1920 were

27


the first to be examined, there may have been an over-representation, amongthem, of a lower frequency of ambulatory BP readings whereby a missingvalue would have greater impact on the total number of readings during thenight. This may be one possible explanation to the higher degree of exclu-sion in this group. More importantly, the subjects who were excluded didnot differ from the study population regarding office BP level, prevalence ofdiabetes or history of myocardial infarction.

The subsample of the population with echocardiographic data, was con-stituted by the first 583 consecutive subjects in the original study popula-tion, as previously described,[98] and not subject to selection.

In Papers III and V, subjects treated with antihypertensive agents wereexcluded. This may have induced some selection bias, since untreated indi-viduals can be assumed to be more healthy from a cardiovascular perspec-tive. Therefore, the differences and associations that were found in the anal-yses, may have been somewhat underrated.

28

KRISTINA BJÖRKLUND

Results

Paper I

Reference values for 24-hour ABPM in 70-year-old men -Distribution vs Correspondence criteriaAverage 24-hour BP in the population was 133±16/75±8, and daytime BP140±16/80±9 mmHg, the respective values in untreated subjects being131±16/74±7 and 139±16/79±8 mmHg. Two different approaches wereused to derive an upper limit of normal ambulatory BP in the population.First, in subjects identified as normotensive according to office BP, the 95thpercentiles of the 24-hour and daytime ambulatory BP distributions were142/80 and 153/85 mmHg respectively. Second, an office recording of 140/90 mmHg corresponded to the ambulatory pressure 130/78 (24-h) and137/83 mmHg (daytime) in untreated subjects. When the ambulatory BPlevels were compared regarding ability to predict office hypertension, thenumber of correctly classified hypertensives was higher using the upper lim-

Office OfficeHypertension Normotension

Distribution criteria 24-h ABP ≥142/80 171 (41) 24 (9) 24-h ABP <142/80 244 (59) 246 (91)

Correspondence criteria 24-h ABP ≥130/78 289 (70) 69 (26) 24-h ABP <130/78 126 (30) 201 (74)Total n (%) 415 (100) 270 (100)

Table 3. Agreement between office BP and ambulatory BP in a classification of untreat-ed subjects as hypertensive using different methods to derive upper limits of 24-hourambulatory BP. Numbers are n (%) correctly classified as office normotensive or hyper-tensive according to the criteria used.

29


it of ambulatory BP derived from correspondence criteria, compared withusing the 95th percentile of ambulatory BP in office normotensives (Table3).

Hypertension prevalence and BP controlThe prevalence of hypertension according to office BP was 66%. The mag-nitude of BP control among treated hypertensives according to differenttreatment goals, is shown in Figure 4.

In treated 70-year-old men, 14% had a BP below 140 mmHg systolicand 90 mmHg diastolic. Twenty-eight percent displayed a 24-h ambulatoryBP <130/78 mmHg, a proposed upper limit of normality in this study.According to guidelines at the time when the study was carried out (160/90mmHg), 39% fulfilled the treatment goals. When only the DBP was con-sidered, around 50% of treated subjects reached a normal BP, using any ofthe three limits of normal BP.

01020304050607080

DBPSBP and DBP

Office BP<140/90

Office BP<160/90

24-h ABP<130/78

(%)

01020304050607080

DBPSBP and DBP

Office BP<140/90

Office BP<160/90

24-h ABP<130/78

(%)

Figure 4. Percentage oftreated hypertensives withdiastolic (full bar) and systolicas well as diastolic (light grey)BP control according todifferent BP thresholds.

Paper IIWe identified 66 nondippers and 991 dippers in the population of 70-year-old men. The SBP level in the two groups during 24 hours is illustrated inFigure 5. However, diabetes was more common in nondippers (26%) thanin dippers (14%). Extreme dipping occurred in 32% of the population, butextreme dippers showed no differences in metabolic status, cardiac struc-ture or function compared with moderate dippers, and these groups togeth-er were regarded as dippers in the following analyses.

30

KRISTINA BJÖRKLUND

Influence of diabeteson the relationshipbetween nondipping and metabolic risk profile at age 70 yearsTo investigate the effect of diabetes and nondipping, respectively, on meta-bolic status, and the possibility of an interaction between them, the dipperand nondipper groups were divided into groups according to diabetes sta-tus. The most pronounced abnormalities in glucose and lipid metabolismwere restricted to diabetic nondippers. A significant interaction was demon-strated between diabetes and nondipping with regard to BMI, triglycerideand fasting glucose levels, whereby nondipping was associated to these met-abolic aberrations only when diabetes was present (Figure 6). As a conse-quence, we identified a large group of nondippers in this population wholacked major metabolic disturbances.

Fig 5. SBP level in dippers andnondippers. The proportion ofindividuals with hypertensionwas not significantly differentin the nondipper group (74%)compared with the dippergroup (65%).

10 14 18 22 2 660

80

100

120

140

160

Dippers

Nondippers

Time (hour)

SBP

( mm

Hg)

10 14 18 22 2 660

80

100

120

140

160

Dippers

Nondippers

Time (hour)

SBP

( mm

Hg)

NondippingDipping

No Diabetes

Diabetes00,5

1

1,5

2

2,5

3

Serum Triglycerides (mmol/l)

NondippingDipping

No Diabetes

Diabetes00,5

1

1,5

2

2,5

3

Serum Triglycerides (mmol/l)

NondippingDipping

No Diabetes

Diabetes0

2

4

6

8

10

Fasting Plasma Glucose (mmol/l)

NondippingDipping

No Diabetes

Diabetes0

2

4

6

8

10

Fasting Plasma Glucose (mmol/l)

Figure 6. Serum triglyceride and fasting plasma glucose levels in nondippers with diabetes(n=17), dippers with diabetes (n=136), nondippers without diabetes (n=49), and dipperswithout diabetes (n=855).

31


Influence of diabetes on the relationship between nondipping andhypertensive target organ damage at age 70 yearsMeasures of left ventricular geometry and urinary albumin excretion wereused as indices of hypertensive target organ damage. Target organ damagedid not differ between nondippers and dippers in the whole population,but a significant interaction between nondipping and diabetes contributedto an increased left ventricular mass in diabetic nondippers (Figure 7). Theurinary albumin excretion rate was independently related to diabetes, andno interaction between diabetes and nondipping was present.

NondippingDipping

No Diabetes

Diabetes8090

100110120130140150160

LVMI (g/m2)

NondippingDipping

No Diabetes

Diabetes8090

100110120130140150160

LVMI (g/m2)

Figure 7. Left ventricular mass innondippers with diabetes (n=11),dippers with diabetes (n=47), non-dippers without diabetes (n=26), anddippers without diabetes (n=342)

Paper III

Metabolic characteristics at age 50 that predict the development ofwhite-coat and sustained hypertension at age 70Individuals were identified as normotensive (n=188), white-coat hyperten-sive (n=106) or sustained hypertensive (n=308) according to office and

ambulatory BP at age 70 years. Of-fice BP determined at age 50 yearswas significantly and similarly ele-vated in subjects with sustained andwhite-coat hypertension determinedat age 70 years (Figure 8). As illus-

Figure 8. Systolic (white bars) and diastolic(grey bars) BP at age 50 years. * p<0.05 vsnormotensives. NT, normotensives; WC,white-coat hypertensives; SHT, sustainedhypertensives.40

60

80

100

120

140

NT WC SHT

Blo

od p

ress

ure

(mm

Hg) *

*

*

*

40

60

80

100

120

140

NT WC SHT

Blo

od p

ress

ure

(mm

Hg) *

*

*

*

32

KRISTINA BJÖRKLUND

trated in Figure 9, a number of similarities regarding an abnormal glucosemetabolism were observed in white-coat and sustained hypertensives at age50. However, a lower BMI and a more favourable serum CE fatty acidcomposition distinguished subjects who twenty years later were identifiedas white-coat hypertensives from sustained hypertensives.

Office heart rate ↑ ↑ ↑ ↑ Body mass index −(↓) ↑ −(↓) ↑ 1-hour B-glucose (IVGTT)

↑ ↑

K-value (IVGTT) ↓ ↓ 2-hour P-glucose (OGTT)

↑ ↑

Insulin sensitivity index ↓ ↓ 16:0 (Palmitic acid) −(↓) − 18:2 ω-6 (Linoleic acid) −(↑) ↓ Dietary fat intake (↓)

Age 50 years Age 70 years

SHTWC WC SHT


SHTWC WC SHT


SHTWC WC SHTWC SHT

5060708090

100110120130140150

5060708090

100110120130140150 ns <0.05

<0.05

WCNT SHT

LVM

I (g/

m2 )

5060708090

100110120130140150

5060708090

100110120130140150 ns <0.05

<0.05

WCNT SHT

LVM

I (g/

m2 )

Figure 10. Measures of target organ damage in the different subgroups at age 70. LVMI, leftventricular mass index; UAER, Urinary albumin excretion rate; NT, normotensives; WC,White-coat hypertensives; SHT, sustained hypertensives.

UAER

(µg/

min

)

02468

101214161820

02468

101214161820

<0.05<0.05ns

WC SHTNT

UAER

(µg/

min

)

02468

101214161820

02468

101214161820

<0.05<0.05ns

WC SHTNT

Figure 9. Metaboli c variables determined at age 50 and 70 years. ↑ and ↓ indicates difference vs NT, - no difference v s NT, and (↑) or (↓) difference v s SHT. NT, normotensives; WC, white-coat hyperten sives; SHT, sustained hyperten sives.

33


Metabolic characteristics and target organ damage at age 70 insubjects with white-coat and sustained hypertensionAt age 70, both white-coat and sustained hypertensives had an impairedinsulin sensitivity, increased plasma glucose and heart rate, however, bodymass index was lower in white-coat hypertensive subjects (Figure 9). Seven-day dietary records showed that white-coat hypertensives at age 70 had alower fat intake and a higher carbohydrate intake than sustained hyperten-sives.

Furthermore, left ventricular mass and urinary albumin excretion rate, asindicators of hypertensive target organ damage, were only increased in sus-tained hypertensives (Figure 10).

Paper IV

Predictive value of ambulatory vs office BP levelsA total of 172/872 cardiovascular morbid events (2.97/100 PYAR), 34 ofwhich were fatal, occurred during the follow-up period of 9.5 years sincebaseline investigation at age 70 years. In a Cox regression model, adjustingfor antihypertensive treatment at baseline, SBP and pulse pressure, bothoffice and ambulatory, were significant predictors of cardiovascular morbid-ity, whereas DBP did not have any prognostic value.

Figure 11 shows the results from a multivariate Cox regression analysis,

Night PPDay PP24-h PP

OPPNight DBP

Day DBP24-h DBP

ODBPNight SBP

Day SBP24-h SBP

OSBP

0,6 0,8 1 1,2 1,4 1,6 1,8

0,6 0,8 1 1,2 1,4 1,6 1,8

Night PPDay PP24-h PP

OPPNight DBP

Day DBP24-h DBP

ODBPNight SBP

Day SBP24-h SBP

OSBP

0,6 0,8 1 1,2 1,4 1,6 1,8

0,6 0,8 1 1,2 1,4 1,6 1,8

Figure 11. Adjusted hazard ratios and 95% confidence intervals for cardiovascular morbidityduring follow-up. The hazard ratio reflects the risk associated with 1 SD increase of a BPvariable measured at age 70 years. PP, pulse pressure.

34

KRISTINA BJÖRKLUND

where smoking, diabetes, hyperlipidemia, antihypertensive treatment andbody mass index were included as covariates in the model assessing the riskassociated with a 1 SD increase of a BP variable at age 70 years. Twenty-fourhour ambulatory pulse pressure remained the most powerful predictor ofcardiovascular morbidity (hazard ratio (HR) for 1 SD increase in BP 1.32,95% CI 1.15-1.52) and the association was independent of office pulsepressure level. Daytime, night-time and office pulse pressure, and all meas-ures of SBP were significant, but weaker predictors of risk in the multivari-ate analysis.

Figure 12. Cardiovascular event rateaccording to tertiles of 24-hourambulatory SBP and daytime SBPvariabilityat baseline. PYAR, Person-years atrisk.

Predictive Value of BP VariabilityVariability of SBP, reflected by the standard deviation (SD) of the daytimeand night-time SBP was a predictor of cardiovascular morbidity, and therelationship remained after adjustment for other cardiovascular risk factors.The variability of daytime (HR 1.19, 95% CI 1.04-1.37), but not night-time SBP (HR 1.14, 95% CI 0.99-1.31), provided prognostic informationindependently of the 24-hour SBP level. As shown in Figure 12, the inci-dence of cardiovascular events rose with increasing daytime SBP variabilitywithin all tertiles of 24-hour SBP.

Paper V

Metabolic and cardiac risk profile at baseline in 70-year-old subjectswith isolated ambulatory hypertensionSubjects with elevated ambulatory but normal office BP, isolated ambulato-ry hypertension, at age 70 years, were more obese, showed higher plasmaglucose levels during the oral glucose tolerance test, and lower insulin sensi-

IIIIII III

III01234

5

Inci

denc

e ra

te (/

100

PYAR

)

24-hour SBP24-hour SBP variabilityIIIIII III

III01234

5

Inci

denc

e ra

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35


tivity compared with subjects with normal BP according to both office andambulatory readings. The prevalence of smoking did not differ between thegroups. Echocardiographically determined relative wall thickness was in-creased both in subjects with isolated ambulatory and sustained hyperten-sion (Figure 13), whereas only sustained hypertensives showed an increasedleft ventricular mass.

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Prognostic significance of isolated ambulatory and sustainedhypertension for cardiovascular morbidityA total of 72/512 cardiovascular morbid events (2.37/100 PYAR), of which48 were coronary events, 20 strokes and 4 peripheral vascular deaths, oc-curred during the mean follow-up of 6.6 years. The probability of cardio-vascular events was increased in both hypertensive subgroups, as shown inFigure 15. The event rate (/100 PYAR) was 3.14 in sustained hypertensives,2.74 in isolated ambulatory hypertensives and 0.99 in normotensives. Inmultivariate Cox Proportional hazard models, adjusting for the possible con-founding effect of serum cholesterol, smoking and diabetes, both isolatedambulatory and sustained hypertension remained significant predictors ofcardiovascular morbidity, the adjusted hazard ratios being 2.77 (95% CI,1.15-6.68) and 2.94 (95% CI, 1.49-5.82 ) for subjects with isolated andsustained hypertension respectively.

Figure 13. Echocardiographically deter-mined relative wall thickness at baselineinvestigation, age 70 years. * p<0.05 vs NT.NT, normotensives; IAH, isolated ambulato-ry hypertensives; SHT, sustained hyperten-sives.

Figure 15. Kaplan-Meier survival curves forprobability of event-free survival during follow-up. NT, normotensives; IAH, isolated ambula-tory hypertensives; SHT, sustained hyperten-sives.

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36

KRISTINA BJÖRKLUND

Discussion

Ambulatory BP normality - definition andconsequencesNormal reference values of ambulatory BP may be defined using differentapproaches, among which the most common are 1) to evaluate the 24-hourBP distribution in normal populations, 2) to identify the 24-hour BP levelthat by regression analysis corresponds to the upper limit of normal officeBP, or 3) to determine the relationship of ambulatory BP to prognostic out-come of morbidity and mortality. In Paper I, based on a large cohort ofelderly men from the general population, we suggested the reference valuesof 24-hour ambulatory BP derived from correspondence criteria in untreat-ed subjects, 130/78 mmHg, as they resulted in a greater number of correct-ly classified office hypertensives than thresholds derived from distributioncriteria. The upper limit of normal 24-hour ambulatory BP in our popula-tion of 70-year-old men was slightly higher than in the Italian PAMELAstudy of elderly,[117] but in agreement with that which has been proposedbased on other population studies,[118-120] and closely resembling thecut-off values for 24-hour ambulatory BP that best predicted cardiovascularmortality in a study that used a prognostic criterion to define normality.[121]Given the progressive increase in office SBP that is seen with age, the simi-larities between our study population and others, comprised of youngersubjects, were a little surprising. Interestingly though, a tendency for SBP toincrease less with age according to ambulatory BP, has been observed inother populations,[117, 122] and the present findings suggest that similardefinitions as in younger populations may be applicable also in elderly sub-jects.

Indeed, reference values derived from large population studies duringrecent years have been consistent, and the consistencies have made it possi-ble to reach consensus regarding a working definition of normal 24-hourambulatory BP, 130/80 mmHg, and daytime ambulatory BP, 135/85mmHg.[71, 123] These figures for normality were also applied by the SixthJoint National Committee on Prevention, Detection, Evaluation and Treat-

37


ment of High BP (JNC-VI).[103] In contrast, in the 1999 WHO-ISH guide-lines,[20] the reference values for ambulatory BP have been quite strictlydefined, with 120/80 mmHg considered as an upper limit of normal day-time ambulatory BP. These recommendations have been subject to criti-cism,[124] due to the discrepancy between such strict thresholds and theconsistent findings from a large body of population data. Caution has beenraised that application of the WHO guidelines may lead to over-classifica-tion of hypertension, and that treatment costs may have serious implicationsfor the health economy.

Whether we use the reference values recommended by the WHO or con-sensus documents, the current thresholds for normal ambulatory BP maystill be viewed as preliminary, and eventually need to be verified in prospec-tive outcome studies.

Hypertension - prevalence and control in an elderly populationThe fact that the present study was conducted in an elderly population, hasimportant implications for the results. As described in Paper I, the preva-lence of hypertension in the ULSAM population at age 70 years was 66%,similar to what has been shown in health surveys of elderly populations inthe United States,[5] and Great Britain.[125] Despite consistent evidenceshowing that adequate treatment of hypertension in elderly reduces cardio-vascular morbidity and mortality,[17, 126] the present findings (Paper I)corroborate others,[32, 127, 128] in that BP is insufficiently controlled inhypertensive populations. This applies in particular to the SBP componentin elderly, which has started to gain interest as a more important prognosticfactor than the DBP.[29] Although Paper I was not primarily designed toinvestigate BP control, the results suggest that more effort is needed to im-plement current guidelines and treatment goals in clinical practice.

Relationship between office and 24-hour ambulatory BPIn agreement with previous population studies,[117, 129, 130] office andambulatory BPs in Paper I were significantly correlated, with correlationcoefficients of about 0.60 for SBP and DBP. Like our study, most previousinvestigations have found office BP to be higher than ambulatory BP.[129,130] The discrepancy between office and ambulatory BP has been attribut-ed to various factors, such as office BP level, age and sex,[131, 132] but alsoto whether the office BP is measured by a doctor or a nurse.[133] BP meas-urement in the office may induce an alerting reaction, the so-called white-coat effect, reflected by an increase in BP and heart rate.[80]

The office-daytime BP difference has sometimes been used as a surrogatemeasure of the white-coat effect, but since it is not associated with a system-atic office-daytime difference in heart rate, and has shown limited repro-

38

KRISTINA BJÖRKLUND

ducibility,[134] the difference between office and daytime BP does notseem to be a reliable measure of this phenomenon. Furthermore, the office-daytime BP difference is less than 30% of the increase in non-invasive fingerBP measured continuously before and during the clinic visit.[135] Anotherfactor believed to influence the difference between office and daytime BP,is the “regression towards the mean”, when comparing office BP measuredat a single visit with the mean of 24-hour ambulatory measurements.[132]Repeated office measurements may be an approach to reduce the measure-ment error, and the mean of standardised repeated office BP measurementson several occasions is likely to more closely correspond to 24-hour ambula-tory BP.[136]

Nondipping as cardiovascular risk indicatorWe found a high prevalence of diabetes among nondipper subjects in thepopulation of 70-year-old men (Paper II). Impaired diurnal BP patternshave previously been reported in both normotensive and hypertensive dia-betic subjects.[74, 137] An increased sympathetic nervous activity and im-paired glucose tolerance has been found in hypertensive subjects with anondipping BP pattern,[138] and an altered autonomic nervous function,which may be associated with both diabetes and hypertension, has beenproposed as a possible pathophysiological explanation for a blunted noctur-nal BP decline.[139] The possible interrelation between diabetes and non-dipping was further elucidated in Paper II, where an interaction was dem-onstrated between diabetes and nondipping with regard to several impor-tant metabolic risk factors. Similarly, a significant interaction between dia-betes and nondipping contributed to an increased left ventricular mass indiabetic nondippers, implying that signs of organ damage and the mostpronounced abnormalities in glucose and lipid metabolism were restrictedto diabetic nondippers. The findings suggest that nondipping, at least in anelderly population, is a marker of risk mainly when diabetes is present.

The results in Paper II support the hypothesis that the pathophysiologicmechanisms behind an impaired nocturnal BP reduction may, in part, differin diabetic and nondiabetic subjects.[140] In diabetic subjects, the dys-functional autonomic cardiovascular regulation may be the most importantfactor contributing directly to nondipping, whereas it in hypertensive nondi-abetic subjects may be attributed to hypertensive damage to the vascularwall, and subsequent persistent elevation of BP during night-time. Otherfactors suggested to be responsible for a disturbed nocturnal BP pattern,include a high sodium sensitivity,[141] and sleep deprivation.[142]

Our findings that left ventricular mass was not increased in nondiabeticnondippers, compared with dippers, agree with some previous studies[78,

39


79] but disagree with others,[66, 143] although the latter did not reportadjusting for diabetes in their analyses. Further, the studies are difficult tocompare due to several differences in study design and populations. Theconflicting findings may partially depend on the use of varying definitionsof nondipping.

Another general problem is methodological, represented by limited re-producibility of diurnal BP variation and dipping profile.[144, 145] In arecent study, a blunted nocturnal BP reduction confirmed by two separateambulatory BP recordings, and thus reproducible over time, was associatedwith increased left ventricular mass and intima media thickness,[146] sug-gesting that a more careful identification of nondippers may increase thepossibility to find subjects at high risk.

White-coat hypertension and the insulinresistance syndromeHypertension is a well known feature of the insulin resistance syndrome,and metabolic risk factors related to hypertension contribute to the devel-opment of target organ damage and eventually, atherosclerotic diseases. InPaper III, not only sustained hypertensive subjects, but in addition, the 70-year-old men with white-coat hypertension showed impaired insulin sensi-tivity, elevated blood glucose and serum insulin compared with normoten-sives in the cross-sectional analysis. Although clamp insulin sensitivity haspreviously not been documented in a similar study of this size, metabolicaberrations have been reported in white-coat hypertensives by some,[87]but not all[84] previous investigators. In a study by Julius et al,[87] white-coat hypertension was preceded by elevated BP levels since childhood, sug-gesting that predictors of this condition may be possible to identify longbefore the office hypertension is discovered.

In the ULSAM study, we found that subjects characterised as white-coathypertensives at the age of 70, had higher office BP and heart rate, a markerof increased sympathetic activity, and an impaired glucose tolerance, to asimilar degree as sustained hypertensives at the investigation twenty yearsearlier. However, white-coat hypertensives differed from sustained hyper-tensives at age 50 by a lower BMI and a more favourable fatty acid compo-sition in the serum cholesterol esters. The findings that an increased heartrate and disturbances in glucose metabolism were consistent over time inboth white-coat and sustained hypertensives are important, since they sup-port the hypothesis that both of these conditions may originate from a stateof increased sympathetic drive.[147] Sympathetic overactivity is, by some,considered to be a driving force in the development of insulin resistance andan important feature of borderline hypertension in its early stage.[148]

40

KRISTINA BJÖRKLUND

It is important to remember that most previous studies have used officeBP to assess hypertension. This is also applicable for several studies where anincreased heart rate has predicted the development of hypertension.[149]Indeed, in the present study an increased heart rate predicted both stateswhere an elevated office BP was observed at age 70, that is, if not ambulato-ry BP monitoring would have been performed, both of these groups wouldhave been classified as “hypertensive”. However, in our population, the hy-pertension that persisted throughout the day was the state characterised bythe highest risk of target organ damage.

Although the two hypertensive groups in our study of elderly men showedsimilarities regarding metabolic risk profile over time, the severity of targetorgan damage, reflected by left ventricular mass and urinary albumin excre-tion rate, was greater only in subjects with sustained hypertension in thecross-sectional analysis (Paper III). Therefore, it might be interesting to spec-ulate about possible mechanisms whereby one of the hypertensive groupsmay have been protected from developing sustained hypertension and organdamage over 20 years of follow-up, but not against becoming insulin resistant.

At age 50, the serum cholesterol fatty acid composition, although morefavourable, operated in an environment of increased sympathetic tone inthe white-coat hypertensive subjects. The metabolic risk profile at baselinewas otherwise similar in white-coat and sustained hypertensives, with theexception that body mass index was not higher in white-coat hypertensivesthan in normotensives. This was also observed twenty years later, when white-coat hypertensives were characterized by impaired insulin sensitivity, butsustained hypertensives were slightly more affected by the entire insulinresistance syndrome, with increased abdominal obesity, body mass indexand serum proinsulin levels.

In our study (Paper III), it seemed as if an increased sympathetic drive, inorder to constitute a predictor of sustained hypertension and more pro-nounced metabolic disturbances, had to act in combination with a higherbody mass and less favourable fatty acid profile. The absence of these addi-tional factors, as seen in the white-coat subjects, may have reduced the risk,and resulted in a “moderately severe” state of the insulin resistance syn-drome, devoid of a persistently increased BP and target organ damage. Wecan only hypothesize whether the lower body mass index observed in thewhite-coat hypertensives mainly was a marker of life style factors, or possi-bly also an indicator of a different genetic predisposition which togetherwith the fatty acid profile put these subjects at another metabolic and cardi-ovascular risk level.

41


Fatty acids and BPFatty acids in serum may influence the vascular system and BP level throughseveral possible mechanisms. A previous experimental study,[150] showedthat sympathetic nervous activity in humans was stimulated by an increasein plasma fatty acid concentration. Furthermore, the circulating free fattyacid levels seem to be associated with both the endothelial function[151]and insulin mediated vasodilation.[152] The fatty acid composition of se-rum cholesterol esters partly reflects the dietary fat quality over the previousweeks,[153] but also depends on genetically determined differences in fattyacid uptake and metabolisation.[56] A randomised controlled study previ-ously showed that compared with a control diet, a diet rich in polyunsatu-rated fat induced a significant increase in the proportion of linoleic acid,and decrease in saturated fatty acids in the serum cholesterol esters, suggest-ing that the serum fatty acid profile can be modified by dietary chang-es.[154]

A high-fat diet has been found to impair endothelial function,[155, 156]and the fatty acid composition of serum lipids is related to endothelium-dependent vasodilation,[157] as well as BP level.[158, 159]

In Paper III, subjects who twenty years later were identified as white-coathypertensives, showed a significantly lower proportion of palmitic acid (16:0),and higher proportions of linoleic acid (18:2 ω-6), indicating a lower intakeof foods containing saturated fat and higher relative intake of vegetable fat,compared with those men who later developed sustained hypertension. Thisfatty acid composition can be regarded as more favourable, since saturatedfatty acids are associated with insulin resistance[55] and adversely affectsthe endothelium-dependent vasodilation,[157] while unsaturated fatty ac-ids, such as linoleic acid, have positive effects on cell membrane fluidityand presumably, function.[160]

The lower proportions of long-chain ω-3 fatty acids, commonly regardedas favourable, in white-coat hypertensive subjects at age 50, may be ex-plained by the fact that a high proportion of linoleic acid in serum canreduce the levels of eicosapentaenoic and docosahexaenoic acid through adecreased conversion of α-linolenic acid to long-chain ω-3 fatty acids, sincethese series are competitors for the same enzymatic systems.[153] Previousdata have shown, that the serum fatty acid composition of 70-year old menreflects that 20 years earlier,[161] implying that subjects with a more fa-vourable dietary fat intake at age 50 maintain these habits. In Paper III, thiswas supported by the observation that white-coat hypertensive subjects hada more favourable fatty acid pattern in serum lipids at age 50, a lower self-reported total fat intake at age 70 and a lower BMI that consisted overtwenty years.

In the ULSAM study, longitudinal relationships have previously been found

42

KRISTINA BJÖRKLUND

between the fatty acid composition in serum cholesterol esters and left ven-tricular hypertrophy.[162] Although there is no established pathophysiolog-ical explanation to this observed relationship, hypothetical mechanisms maybe suggested. Since endothelial dysfunction is related to left ventricular hyper-trophy,[163] and the serum fatty acid profile is associated with endotheli-um dependent vasodilation,[157] this may represent a possible link betweenthe fatty acid profile, sustained hypertension and left ventricular hypertro-phy.

Prognostic value of 24-hour ambulatory BP

The role of ambulatory SBP and pulse pressure in risk assessmentIn agreement with previous studies,[9-12] findings from the ULSAM popu-lation (Paper IV) indicate that 24-hour ambulatory BP is an important pre-dictor of cardiovascular morbidity independent of office BP and other es-tablished cardiovascular risk factors. More specifically, 24-hour ambulatorySBP and pulse pressure showed the strongest predictive power, while theDBP component did not contribute with any prognostic information (PaperIV). The fact that these results were achieved from a longitudinal analysis ofan elderly population has important implications for the results. The prog-nostic value of SBP is known to increase with age, and SBP is an importantpredictor of cardiovascular morbidity and mortality in elderly.[6, 23]

Epidemiological data suggest that BP components may influence cardio-vascular risk differently at different ages,[29, 164, 165] shifting from DBPto be of importance below 50 years of age, to SBP and pulse pressure aboveage 60. In recent observational studies, using office[27, 28] or ambulato-ry[166, 167] recordings, pulse pressure has emerged as a major determinantof cardiovascular risk. In contrast with findings from the Syst-Eur Study,[12]daytime, but not night-time SBP was associated with a significantly increasedcardiovascular risk in the ULSAM population (Paper IV). Furthermore, thenight-day SBP ratio provided prognostic information independent of the24-hour BP level in the Syst-Eur Study, whereas no such association wasdetected in ULSAM. The explanation to these discrepancies is not quitesimple, but one possible reason may be found in the different characteristicsof the populations studied. While Syst-Eur consisted solely of elderly pa-tients with isolated systolic hypertension, thus being at high risk for cardio-vascular events, we studied elderly men from the general population in UL-SAM. Data from Paper II further indicated that target organ damage wasonly present in diabetic subjects with nondipping, suggesting that in a pop-ulation setting, a reduced nocturnal BP decline may primarily be a riskmarker in subjects with diabetes.

43


Aortic stiffness - pathogenetical mechanisms behind an increasedpulse pressureBP consists of a steady component, expressed as the product of total periph-eral resistance and the cardiac output, and a pulsatile component, deter-mined by ventricular ejection and arterial stiffness.[168] DBP and SBP rep-resent the extremes of the fluctuations during the cardiac cycle, and pulsepressure is the difference between them. Whereas DBP reflects the mean,steady BP component more closely than SBP, the latter has a stronger associ-ation with pulse pressure.

Arterial compliance is defined as the relationship between changes indistending pressure inside the artery, and the concomitant change in radius,or volume. The relationship is non-linear, and depends on BP level and thecomposition of the arterial wall. The arterial wall is a mixture of smoothmuscle cells, collagen and elastin fibres, and as BP increases, the tension onelastin fibres, which are highly distensible, is transferred to collagen fibres,which are less distensible, leading to a stiffer arterial wall with increasing BP.Arterial compliance constitutes an important physiological mechanism,through the so called “Wind-kessel function”, whereby pulsatile flow in thelarge arteries is transformed into a steady flow in the peripheral tissues tomaintain organ perfusion.[168]

With aging, the elastic properties of the arteries decrease, a developmentthat may be accelerated by hypertension and arteriosclerosis. As the largearteries stiffen, they become less distensible, causing a quicker return of thebackward pressure wave towards the heart,[34] and a subsequently higherSBP and lower DBP. These age-related changes may have deleterious conse-quences for the heart, since the coronary perfusion is reduced while theincreased SBP causes a simultaneously increased myocardial oxygen demand,predisposing to left ventricular hypertrophy and myocardial ischemia.[35]The increased SBP and pulse pressure, being a result of as well as causing afurther accelerating arterial damage, creates a vicious cycle.

There are different methods of measuring aortic stiffness. The speed ofwave travel in the aorta, pulse wave velocity, can be indirectly non-invasive-ly estimated by applanation tonometry, whereby the pulse wave is recordedat the radial or carotid artery, and a computerised process is used to generatean aortic pressure wave-form.[34] Aortic stiffness assessed by pulse waveanalysis has recently been shown to predict cardiovascular morbidity[169]and mortality[170, 171] in population studies. Due to a difference be-tween the pulse pressure in the aorta and the upper limb arteries whenmeasured clinically, the adverse effects of aortic stiffening are underestimat-ed by measurement of brachial artery pressure by sphygmomanometer.[35]However, this difference is most evident in younger subjects, and may evenbe irrelevant in elderly.[168, 172] Thus, the use of brachial arterial pulse

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KRISTINA BJÖRKLUND

pressure as a surrogate measure of arterial stiffness seems appropriate inelderly. In addition, our study of 70-year-old men as well as previous longi-tudinal studies,[27, 28, 167] suggest that brachial arterial pulse pressurerepresents a more sensitive cardiovascular risk marker than SBP and DBP inelderly, indicating that this measure provides useful prognostic value in thepopulation at large.

BP variability and prognosisIn Paper IV, a high daytime SBP variability measured at baseline was asignificant predictor of cardiovascular morbidity in 70-year-old men after 9years of follow-up, independent of other established cardiovascular risk fac-tors and 24-hour ambulatory BP level. A similarly positive longitudinal asso-ciation between daytime systolic, but not diastolic, BP variability and cardi-ovascular mortality was previously found in a Japanese population,[70] where-as the relationship to an adverse outcome did not remain significant in themultivariate analysis in an earlier Italian study.[173] An increased BP varia-bility has been directly associated with age and BP level.[174, 175]

Autonomic cardiovascular regulatory mechanisms, in particular the arte-rial baroreflex function, are important determinants of fluctuations in BP,and an impaired baroreflex sensitivity is more common in elderly and inhypertensive subjects. The sensitivity of the arterial baroreflex is inverselyrelated to the degree of BP variability and directly related to the heart ratevariability. The baroreflex sensitivity, a marker of the capability to reflexlyincrease vagal activity and decrease sympathetic activity in response to anincrease in BP, was recently shown to predict cardiac mortality in patientsafter a myocardial infarction.[176] An imbalance in the autonomic nervoussystem, with relatively high sympathetic and low vagal activity may thusrepresent one explanation for the adverse outcome related to increased BPvariability in our study (Paper IV). Previous studies have indicated that tar-get organ damage, evaluated as left ventricular hypertrophy, was greater withincreasing BP variability in hypertensive subjects, independent of 24-hourBP level.[65, 66] However, from these cross-sectional investigations it wasdifficult to determine whether the BP variability was the cause or effect ofthe organ damage.

In the ULSAM study, we assessed the long-term BP variability as thestandard deviation of hourly BPs over day and night respectively. The inter-mittent measurements derived from non-invasive ambulatory BP monitor-ing may be a limitation, as they only roughly estimate long-term BP chang-es. In addition to intra-arterial BP monitoring, the more recently developednoninvasive continuous beat-to-beat finger BP recording devices might pro-vide a more precise evaluation of different BP frequency components.[177,178]

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Predictive value of isolated ambulatory andwhite-coat hypertension

Isolated ambulatory hypertensionWhen there is a discrepancy between office and ambulatory BP, the progno-sis has been suggested to be more closely related to ambulatory BP.[81] Ofthe two situations where office and ambulatory BP may be discordant, thestate with normal office but elevated ambulatory BP probably representsthe greatest challenge. This is partly due to the fact that the knowledge ofthis condition is very sparse, and partly because it is not detected by theestablished hypertension screening instrument; office BP measurement. Twoprevious studies have shown that normal office but elevated ambulatory BP,or as we prefer to call it, “isolated ambulatory hypertension”, has a noticea-ble prevalence in the general population, and is associated with cardiac andarterial organ damage to a similar degree as sustained hypertension.[90, 91]

A higher daytime than office BP was recently observed at baseline in alarge proportion of elderly hypertensive subjects in the Second AustralianNational BP Study, a randomised-outcome trial.[179] Moreover, a retro-spective analysis of treated hypertensive subjects in the SHEAF (Self-Meas-urement of BP at Home in the Elderly: Assessment and Follow-up) study,showed that cardiovascular risk profile and history of cardiovascular diseasein patients with “isolated home hypertension” resembled those in patientswith uncontrolled hypertension.[180] Although these cross-sectional andretrospective studies suggest that isolated ambulatory hypertension is associ-ated with an increased cardiovascular risk, longitudinal data regarding car-diovascular outcome are thus far lacking.

In Paper V, we present evidence that isolated ambulatory hypertension isa predictor of cardiovascular morbidity, independent of other establishedcardiovascular risk factors. Our study was performed in 70-year-old menfrom a population-based cohort, who had no antihypertensive treatment atbaseline, and were followed for 8.4 years. At baseline, subjects with isolatedambulatory hypertension had more abdominal obesity, and higher plasmaglucose levels than normotensives. Further, a subanalysis of echocardiographicdata showed, in agreement with previous studies,[90, 91] signs of cardiachypertrophy in subjects with isolated ambulatory hypertension.

The possible mechanisms behind an elevated ambulatory daytime BP,but normal office BP, are not fully understood, but subjects with this BPpattern have previously been characterised as older,[90, 181] more oftenmale,[90, 180, 181] and former smokers.[180, 181] Smoking elicits anacutely increased BP which becomes apparent during daytime BP monitor-ing, while individuals are told to refrain from smoking before a visit to theclinic.[182] In the ULSAM population, we found no differences in smok-

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KRISTINA BJÖRKLUND

ing prevalence between the subgroups defined in Paper V, whereas genderand age differences were not possible to investigate due to the study design.Other factors that may influence BP level during daytime include physicalactivity, and working conditions. In an analysis of self-reported leisure-timephysical activity at baseline, we found no differences between the subgroups.Further, since the ULSAM population at age 70 had passed the age-limit forretirement, we did not expect to find working condition as an importantcontributor to differences in daytime BP patterns.

Subjects in ULSAM were identified as normotensive or hypertensive basedon the mean of two BPs taken at a single visit. As for white-coat hyperten-sion, the number of correctly classified office hypertensives may increasewith an increased number of BP readings. However, according to a previousstudy, the accuracy of office BP measurements in isolated ambulatory hy-pertension was not improved by repeated clinic visits.[181] Thus, althoughPaper V leaves some unanswered questions to be further investigated, thefindings add to the evidence that office BP measurement as a method hasshortcomings, and that the prognostic implications may be serious.

White-coat hypertension and prognosisAlthough much attention has focused on white-coat hypertension during

recent years, there are very limited data regarding the prognostic signifi-cance of this presumably innocent condition. Verdecchia et al showed, thatwhite-coat hypertensive subjects had a risk of cardiovascular events not dif-ferent from that in normotensive controls,[10] however the study was limit-ed by a short follow-up time. In a later extension of that Italian study, theoutcome in white-coat hypertension, either similar to normotensives or tosustained hypertensives, was dependent on the definition used to identifywhite-coat hypertensive subjects.[88] In another study,[89] using intra-arte-rial BP monitoring, patients with white-coat hypertension was associatedwith substantially reduced risk of cardiovascular events over 10 years offollow-up, compared with patients whose BP was sustained throughout 24hours.

Figure 16 illustrates the office and ambulatory BPs in untreated subjectsfrom ULSAM, and the four subgroups possible to identify according tothese monitoring methods. Ninety-six cardiovascular morbid events occurredover 9.4 years of follow-up since the baseline investigation at age 70 years.Preliminary results (unpublished data, 2002) from a multivariate Cox Pro-portinal Hazard regression, adjusting for smoking, diabetes and serum cho-lesterol levels, showed that the hazard ratio for cardiovascular morbidity washighest in sustained hypertension (HR 2.79, 95% CI 1.49-5.21) followedby isolated ambulatory hypertension (HR 2.44, 95% CI 1.05-5.66). White-coat hypertension was not a significant predictor of cardiovascular disease inthe ULSAM population (HR 1.79, 95% CI 0.82-3.87), thus corroborating

47


the two previous prospective studies available today.[10, 89] The results arealso in line with previous findings in ULSAM (Paper III), where signs ofhypertensive cardiac and renal damage were similar in white-coat hyperten-sives and normotensives.

Fig 15. Distribution of office and daytime ambulatory SBP in untreated subjects (n=684) ofthe ULSAM population at age 70 years. HR indicates adjusted Cox proportional hazard ratiosfor cardiovascular morbidity in subgroups according to normal or abnormal office and daytimeBP. All groups compared with nomotensives (HR 1.00).

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Clinical relevanceThe present findings, in a population of elderly men, support previouslypublished data suggesting that 24-hour ambulatory BP is a stronger predic-tor of cardiovascular morbid events than office BP, and speak in favour of amore wide-spread clinical use of 24-hour ambulatory BP monitoring.

Despite the advantages of the method, ambulatory BP monitoring is usedto a limited extent in the clinic, and in clinical trials, and it is still mainlyregarded as a research tool.[20] Reasons for this might be practical issuessuch as inconvenience to the patient caused by disturbed sleep at night, andcost aspects associated with the monitoring procedure. Furthermore, therehas been a lack of knowledge regarding interpretation of the measurementsand limited data about prognostic value of the method. Not until recently,reference values for normal 24-hour BP were suggested,[71] and with in-creasing prognostic information, these recommendations may need revision.However, the reference values of ambulatory BP based on the present studyof an elderly population (Paper I), are close to the current working defini-

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KRISTINA BJÖRKLUND

tions, suggesting that these may be appropriate to use also in the elderly.It has been proposed, that a large number of repeated, standardised office

BP recordings may provide a mean BP close to the “true” BP level obtainedby 24-hour ambulatory BP monitoring. This may be partially accurate, butwe, and others[70] have shown that 24-hour ambulatory BP monitoringprovides additional prognostically important information, represented byBP variability (Paper IV), that can not be obtained by office BP. Findingsfrom the present study also suggest that office BP measurement, may insome subjects, fail to identify daytime ambulatory hypertension (Paper V), acondition with a fairly large prevalence in the present study population of70-year-old men, and associated with an increased incidence of cardiovas-cular events.We have, in agreement with others,[12] demonstrated that ambulatory SBPis a stronger predictor of cardiovascular events than office SBP. The Syst-EurStudy, conducted in an elderly hypertensive population, showed that SBP inparticular may be overestimated by office readings.[12] Elderly are moreprone to postural and postprandial hypotension, and the symptoms mayworsen by a high susceptibility to the adverse effects of antihypertensivedrugs. Misclassification of hypertension leading to unnecessary medicationis therefore particularly harmful in older patients. Furthermore, an issuethat previously has been raised,[183, 184] concerns the potential overtreat-ment of hypertension in society, due to inaccurate treatment decisions insubjects with white-coat hypertension. The hypothesis that white-coat hy-pertension is a harmless condition, with an associated cardiovascular risksimilar to that in normotension, is now supported by two longitudinal stud-ies[10, 89] and preliminary results (unpublished data, 2002) from the UL-SAM population. Furthermore, the only study that has investigated the ef-fects of antihypertensive teatment on prognosis in white-coat hypertension,showed no benefit of treatment.[185]

To correctly diagnose, or to treat white-coat hypertension due to igno-rance, is a matter of benefit for the patient, and cost for society, representedby on one hand expenses for drugs, and on the other, for an ambulatorymonitoring procedure. It was recently shown, that by using ambulatory BPmonitoring instead of office BP measurement as a basis for drug prescrip-tion, significantly less drug treatment was prescribed, and the cost for am-bulatory BP measurement were offset by the savings from less drug prescrip-tion and fewer clinic visits.[186]

In summary, the clinical relevance of the present findings is important.Considering the strong prognostic value of ambulatory BP, it might be rea-sonable to suggest the performance of at least one ambulatory BP monitor-ing session in a hypertensive patient, at some point of time, to gain moredetailed information on the total risk profile. In non-diabetic subjects, a BPmonitoring during 12 hours may be enough to identify subjects with white-

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coat hypertension, who are not at increased cardiovascular risk, and in whomtreatment is not necessary. In contrast, the present findings propose, that afull 24-hour ambulatory BP monitoring should be recommended in pa-tients with diabetes, since the night-day BP difference may be a marker ofincreased risk primarily in this patient group. Elderly subjects, in particular,might benefit from a health check-up, where daytime ambulatory BP mon-itoring could be included to identify subjects with white-coat, as well asisolated ambulatory hypertension. Thus, given the independent predictivevalue of the mean daytime ambulatory BP in the general population, differ-ent approaches to the use of ambulatory BP monitoring in different patientgroups may reduce the unnecessary inconvenience to the patient, represent-ed by night-time BP monitoring.

A final important clinical implication of the present thesis does not con-cern any new findings, but the well known fact that hypertensive patientsare insufficiently treated, as observed in Paper I. To improve hypertensioncontrol is a main future goal, and 24-hour ambulatory BP monitoring maybe a helpful tool in that effort. Further, many elderly with moderately orborderline elevated BP still do not receive any treatment, as demonstratedin Paper V, although this condition is associated with a substantially in-creased risk in the elderly.

Strengths and limitations of the studyThe most obvious limitation of this study, is the lack of women in the studypopulation. When ULSAM was initiated in the beginning of the 1970´s,one of the aims was to identify risk factors for cardiovascular disease in ahigh risk population, at that time typically represented by middle-aged men.It is now known, that although coronary heart disease is not as common inwomen as in men during middle-age, the risk increases substantially aftermenopause, and coronary heart disease in fact constitutes the leading causeof death in women. This age-dependent risk increase has partly been attrib-uted a possible protective effect of estrogen in pre-menopausal women.[187]

Age-dependent gender differences also apply for hypertensive disease. Datafrom observational population studies have indicated that women show alower BP, both office and ambulatory, than men up to the fifth decade ofage.[5, 130] This does however not reduce the role of hypertension as animportant cardiovascular risk factor in elderly women. Indeed, the fact thathypertension has similar prevalence rates and has become a similarly strongcardiovascular risk factor in women as in men at the age of 70, suggest thatthe present findings may be applicable also in women. However, some cau-tion should be taken regarding generalizability of these results, until theyhave been confirmed in elderly women.

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Regarding the cohort, we might assume, that subjects who participated inthe re-investigation at age 70, were somewhat healthier than those who didnot participate, and this may have lead to some underestimation of theassociations found. Another important limitation of the present study, is thelack of withdrawal of antihypertensive medication before the investigations.This is however a common drawback of cohort studies of this size.

All the papers in this thesis are based on data derived from the generalpopulation, resulting in limited selection bias. The population studied washomogeneous, comprising men of similar age and from a well-defined geo-graphical area. The characteristics of ULSAM as being representative of thegeneral population, and including both hypertensive and normotensive sub-jects, gave us the opportunity to investigate the prognostic significance ofBP for cardiovascular disease in elderly at different levels of normal andelevated BP, and to further evaluate the prevalence, associated risk profileand predictive value of isolated ambulatory hypertension, requiring 24-hourambulatory BP data from subjects defined as normotensive according tooffice BP.

Hypertension is a complex state, and despite being an independent cardi-ovascular risk factor, the strength of association with cardiovascular diseasemay be related to other components of the insulin resistance syndrome, aswell as lifestyle factors. The broad multifactorial approach of the presentstudy material, including metabolic parameters, dietary information anddata on physical activity, therefore makes the ULSAM study particularlyvaluable for an investigation into epidemiological aspects of hypertension.

Future perspectivesThe growing evidence from this (Paper IV), and previous studies, demon-strating that pulse pressure is a powerful predictor of cardiovascular morbid-ity and mortality in elderly, leads to the question whether a treatment regi-men that reduces not only mean BP, but also pulse pressure, may preventadverse events in elderly with this hypertensive subform. This question shouldbe answered by randomised clinical trials, designed to evaluate the specificeffect of conventional as well as new antihypertensive drugs on reducinglarge artery stiffness, as this should be the target of treatment.[188] Theinclusion criteria must be based on elevated SBP or pulse pressure, as al-ready has been done in Syst-Eur and Syst-China,[30, 31] and the efficacy oftreatment should be measured in terms of decrease in pulse pressure. Com-mon antihypertensive drugs, such as thiazide diuretics, ß-blockers and calci-um channel blockers, lower SBP as well as DBP, but in subjects with a widepulse pressure, a further decrease in DBP may be detrimental for the coro-nary perfusion. In contrast, low-dose nitrates have been shown to reduce

51


arterial stiffness and lower pulse pressure without affecting the DBP. Anoth-er target of treatment may be to modify arterial structure and thereby re-duce pulse wave velocity, possibly by inhibiting collagen accumulation, whichhas been achieved experimentally through blockade of angiotensin II (type1)receptors.[188]

The adverse prognostic outcome associated with isolated ambulatory hy-pertension presently observed in the ULSAM study (Paper V) illustrates thelimitations of office BP as a screening instrument, and addresses the impor-tant question of potential undertreatment of these patients. Although itseems likely that these patients would benefit from antihypertensive treat-ment, this should be a matter for investigation in future randomised clinicaltrials.

Large clinical intervention trials have a huge impact on hypertension treat-ment policy. It is therefore essential that BP in these trials is measured cor-rectly. Although the standardized office measurement procedures are fol-lowed, there may be differences in treatment effects during day and night,that are not revealed by a conventional office measurement. Such differenc-es may be crucial for an accurate interpretation of the trial, as recentlyillustrated in a substudy of ambulatory BP in the Heart Outcomes Preven-tion Evaluation (HOPE) trial.[189] In all future clinical trials evaluatingeffect of antihypertensive treatment, ambulatory BP monitoring should there-fore be performed in a representative subsample of the study population.Furthermore, future intervention trials should, to a larger extent, use 24-hour ambulatory BP as inclusion criteria and efficacy parameter in relationto cardiovascular outcome measures.

The importance of cost-benefit related issues for the clinical implicationsof ambulatory BP monitoring has already been mentioned. With more focusdirected towards health economy, future studies may be able to show notonly clinical, but also economical benefits of an increased use of 24-hourambulatory BP monitoring. Finally, the potential significance of a correctdiagnosis and an efficient hypertension management for the quality of lifeof the patient, can not be overestimated.

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Conclusions

I. Reference values of ambulatory BP were established in a large cohort of70-year-old men, and the upper limits of normal ambulatory BP in thiselderly population were in agreement with those suggested in current guide-lines. The study confirmed previous findings of a high prevalence of hyper-tension in elderly, and indicated that BP was inadequately controlled inelderly treated hypertensive subjects.

II. An interaction was demonstrated between nondipping and diabetes,regarding several metabolic parameters as well as echocardiographically de-termined left ventricular mass. Thus, we identified a nondipping high-riskgroup being diabetic, and a group of nondippers with a normal metabolicstatus and a lack of organ damage, implying that nondipping, at least inelderly, is a marker of increased risk primarily in the presence of diabetes.

III. Several metabolic disturbances at age 50 predicted both white-coat andsustained hypertension and were consistent over twenty years of follow-up. How-ever, the development of white-coat hypertension was preceded by lowerBMI and a more favourable serum CE fatty acid composition at age 50. In across-sectional analysis at age 70, only subjects with sustained hypertension showedsigns of organ damage. Thus, an unfavourable dietary fat intake and obesity maybe important contributors to sustained hypertension and organ damage.

IV. In a longitudinal analysis, SBP and pulse pressure, but not DBP, weresignificant predictors of cardiovascular morbidity. Twenty-four-hour and day-time ambulatory pulse pressure had the strongest predictive value, inde-pendently of office BP, antihypertensive medication, hyperlipidemia, diabe-tes, smoking and BMI. The results indicate that pulse pressure is an importantpredictor of cardiovascular morbidity in elderly, and further that ambulatory BPis superior to office BP in evaluating cardiovascular risk in an elderly population.

V. Subjects with isolated ambulatory hypertension showed metabolic ab-normalities and signs of cardiac hypertrophy in the cross-sectional analysis.More importantly, isolated ambulatory hypertension was a significant inde-pendent predictor of cardiovascular morbidity. These findings suggest that24-hour ambulatory BP may disclose important prognostic information alsoin subjects with a normal office BP.

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Acknowledgements

I wish to express my sincerest gratitude to everyone who has contributed tothis work in different ways. My special thanks go to

Lars Lind, my principal supervisor, for guiding me into the field of cardio-vascular research, for his unlimited enthusiasm and bright scientific mind,and for patience and support whenever needed,Hans Lithell, head of the Section of Geriatrics, my mentor and supervisor,for sharing his extensive knowledge of hypertension as well as good adviceabout life in general, for consistent encouragement and nice chats about lifeafter the thesis, and without whose outstanding persuasive skill I might havestayed in Trollhättan to do AT instead of writing this thesis,Bengt Vessby, head of the Section for Clinical Nutrition, co-author and pos-sessing invaluable knowledge of fatty acids, for saving me from getting lostin the fatty acid swamp,Lars Berglund and Rawya Mohsen, for excellent statistical advice and exper-tise regarding data handling in general, and ULSAM in particular,Margareta Öhrwall, head of the Metabolic Ward and expert on treatment ofobesity, for being my clinical tutor and turning theory into clinical practice,Previous or current PhD students, colleagues and friends at the Section ofGeriatrics; Ann-Cristin, Anu, Arvo, Björn, Claes, Johan S, Johan Ä, Kristina D,Lena, Lennart, Liisa, Karin, Merike, Meta and Per-Erik, and at the Section ofClinical Nutrition Research; Achraf, Agneta, Anders, Anette, Annika, Brita,Cecilia, Eva, Johanna, Samar and Ulf, and the “newcomers” Bernice, Kristin,Klara, and Martin, to all for contributing to the friendly and warm atmos-phere, for good laughs and interesting conversations over numerous coffee-breaks, to those who have participated in the “doktorandklubben”; a specialthanks for dynamic and constructive discussions, the lunch-team, for get-ting me used to extravagant long lunch-breaks - I will miss them, either wehad thai food or lukewarm sushi, Johan S, Johan Ä and Ulf; for letting mejoin in and sometimes win the office-golf competitions, Johan Ä; for greattravel-company to London, Milan and New Orleans, and for saving mefrom annoying males, whether my annoyance was justified or not,Jan Hall, particularly for skillful performance of the ambulatory BP moni-toring, and Siv Tengblad, Eva Sejby and Barbro Simu, for outstanding labora-tory work, and professional arrangement of parties,

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KRISTINA BJÖRKLUND

Bertil Andrén, for co-authorship, and for carrying out all the echocardio-graphic examinations,Birgitta and the entire staff of nurses and dieticians at the Metabolic Ward,for taking such good care of the study participants and creating a pleasantworking climate,

All the brave Uppsala-men, for participating in the ULSAM study, withoutyou there would definitely not have been a thesis,

Anna-Pia, Eva, Frida, Jenny and Lotta, for keeping me updated on the worldoutside Uppsala, for great friendship and late nights out with the girls,Gabriella, for being an awesome friend, and for sharing enthusiasm overBach´s Concerto for two violins although it is really too complicated for us,Franziska, my dear friend and colleague, for always being there, and forsharing my devotion for travelling, but also for sharing unpleasant Mexicanexperiences of having mice in bed at night,Erik, my dear older brother, for letting me for once be the first; to completea thesis, and together with Lotta and Sofia, for being an important part of myprecious family,My dear mother and father, for being the best of parents, for all your love andgenerosity, for always believing in me and supporting me in everything,and Carl, without whom I might not have stayed in Uppsala to write thisthesis, for making my heart beat a little faster, for making me laugh everyday and for being my best friend, for endless encouragement and valuablehelp with thesis cover design – I love you.

This work was supported by grants from the Foundation for Geriatric Re-search, Ernfors Fund for Diabetic Research, Swedish Medical Research Coun-cil (grant no. 5446), the Swedish Association against Heart and Lung Dis-ease, the Geriatric Fund, Trygg Hansa, “Förenade Liv” Mutual Group LifeInsurance Company, the Swedish Council for Planning and Coordination ofResearch, the Thuréus Foundation, and Uppsala University.

The cover illustrates the blood pressure during a common day of the author´s lifemeasured by 24-hour ambulatory BP monitoring.

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