Essential Hypertension

SEMINAR
Seminar
Essential hypertension
Jan A Staessen, Jiguang Wang, Giuseppe Bianchi, Willem H Birkenhäger
Hypertension is a frequent, chronic, age-related disorder, which often entails debilitating cardiovascular and renal
complications. Blood pressure is usually noted in combination with other cardiovascular risk factors. Diagnosis of
hypertension increasingly relies on automated techniques of blood pressure measurement. The pathophysiology of
essential hypertension depends on the primary or secondary inability of the kidney to excrete sodium at a normal
blood pressure. The central nervous system, endocrine factors, the large arteries, and the microcirculation also have
roles in the disorder. Although monogenic forms of blood pressure dysregulation exist, hypertension mostly arises as a
complex quantitative trait that is affected by varying combinations of genetic and environmental factors. Non-
pharmacological strategies can reduce blood pressure. Antihypertensive drug treatment diminishes the complications
of hypertension. The concept that a few major genes will provide the final clue to the pathogenesis of essential
hypertension is an oversimplification that contradicts the heterogeneous nature of this disorder. Further integration of
genetic, molecular, clinical, and epidemiological research could disclose subsets of patients in whom specific
combinations of genetic and environmental factors raise blood pressure, and might lead to more individualised
treatment.
Essential hypertension refers to a lasting increase in blood Epidemiology

pressure with heterogeneous genetic and environmental In cross-sectional and longitudinal population studies,
causes. Its prevalence rises with age, irrespective of the systolic blood pressure increases with age until the eighth
type of blood pressure measurement and the operational decade of life (figure 1). By contrast, diastolic blood
thresholds used for diagnosis (panel 1). In developed and pressure rises only until 50 years of age, after which it
developing countries alike, essential hypertension affects either becomes constant or even decreases slightly. In the
25–35% of the adult population, and up to 60–70% of Framingham Heart Study,1 increasing age entailed a shift
those beyond the seventh decade of life. Hypertension from diastolic pressure to systolic pressure and then to
aggregates with other cardiovascular risk factors, such as pulse pressure as the main predictor of cardiovascular
abdominal obesity, dyslipidaemia, glucose intolerance, risk. Below age 50 years, diastolic pressure was the
hyperinsulinaemia, and hyperuricaemia, possibly because strongest predictor. Age 50–59 years was a transition
of a common underlying cause. period when all three blood pressure indices were similar
We will review developments in the epidemiology, predictors, and from 60 years on, diastolic pressure was
diagnosis, pathophysiology, genetics, and treatment of negatively related to the risk of coronary events, so that
essential hypertension. During the past decade, these pulse pressure became a superior predictor to systolic
disciplines have progressed towards substantial new pressure.1 The finding that in middle-aged and older
insights. Nevertheless, despite relentless research efforts, patients cardiovascular outlook gets worse with raised
the specific causes of essential hypertension remain pulse pressure—rather than mean pressure—is consistent
incompletely understood. We will therefore emphasise the in men and women, in treated and untreated
need for improved integration of multidisciplinary hypertensive individuals,2 and in patients with a history of
research to clarify the pathophysiology of this complex myocardial infarction3 or renal failure.4 Furthermore, in
and multifaceted disorder. older patients with isolated systolic hypertension,
ambulatory pulse pressure is a stronger predictor of
cardiovascular risk than is pulse pressure measured by
conventional sphygmomanometry, whereas mean
pressure regardless of the type of blood pressure
measurement is not predictive.5
Lancet 2003; 361: 1629–41
Search strategy
Studiecoördinatiecentrum, Hypertensie en Cardiovasculaire We identified original research papers, reviews, and editorial
Revalidatie Eenheid, Departement voor Moleculair en comments by going through leading journals that publish
Cardiovasculair Onderzoek, Katholieke Universiteit Leuven, Leuven,
basic and clinical research in the field of hypertension, and
Belgium (J A Staessen MD, J Wang MD); Divisione di Nefrologia
by electronically searching the Medline database. We
Dialisi e Ipertensione, Ospedale San Raffaele, Dipartimento di
directed special attention to papers published since 1997.
Scienze e Techologie Biomediche, Universitá Vita-Salute, Milano,
Italy (Prof G Bianchi MD); and Erasmus University, Rotterdam,
We reviewed consensus documents on automated blood
Netherlands (Prof W H Birkenhäger MD) pressure measurement as well as guidelines for the
management of hypertension. We also looked for research
Correspondence to: Dr Jan A Staessen, Study Coordinating Centre,
developments by discussions with our collaborators and with
Laboratory of Hypertension, University of Leuven, Campus
specialists in the clinical or fundamental aspects of
Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium
cardiovascular medicine
(e-mail: [email protected])
THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com 1629
For personal use. Only reproduce with permission from The Lancet Publishing Group.
SEMINAR
Panel 1: Systolic and diastolic blood pressure thresholds used in clinical medicine
Conventional blood pressure measurement* Automated blood pressure measurement†
Category Boundaries Type of measurement P95‡ Normotension Hypertension
Normotension Ambulatory
Optimum <120/<80 24-h 132/82 <130/<80 >135/85
Normal 120–129/80–84 Daytime 138/87 <135/<85 >140/90
High-normal 130–139/85–89 Night-time 123/74 <120/<70 >125/75
Hypertension Self-recorded
Grade I (mild) 140–159/90–99 Morning 136/85 <135/<85 >140/>90
Subgroup borderline 140–149/90–94 Evening 138/86 <135/<85 >140/>90
Grade II (moderate) 160–179/100–109 Both 137/85 <135/<85 >140/>90
Grade III (severe) >180/>110
Isolated systolic hypertension >140/<90
Subgroup borderline 140–149/<90
Blood pressure thresholds are in mm Hg. *Consensus classification proposed by European Society of Hypertension/European Society of Cardiology
guidelines.10 †Classification proposed at the 8th International Consensus Conference on Ambulatory Blood Pressure measurement (Sendai, Japan,
October 2001). ‡Mean of 95th percentiles in subjects who on conventional blood pressure measurement were normotensive in large-scale studies.
Most epidemiologists6,7 share the point of view that the European and American people is coronary heart disease,
relation between risk of cardiovascular complications and whereas in Asian and older people it is stroke.8 Black
blood pressure is continuous, without a threshold above people tend to have higher blood pressure and
which the rate of disease would suddenly increase. The hypertension-related mortality rates than other
main complication of hypertension in middle-aged individuals.9 The Framingham investigators reported that
Men (n=833) Women (n=859)
150
Systolic Conventional BP at home Systolic
Daytime ambulatory BP
140
130
120
Blood pressure (mm Hg)
110
100
Diastolic Diastolic
90
80
70
60
50
4 9 4 9 4 9 4 9 4 9 4 9 4 4 4 9 4 9 4 9 4 9 4 9 4 9 4 4
–1 5–1 0–2 5–2 0–3 5–3 0–4 5–4 0–5 5–5 0–6 5–6 0–7 5–8 –1 –1 –2 –2 –3 –3 –4 –4 –5 –5 –6 –6 –7 –8
10 1 2 2 3 3 4 4 5 5 6 6 7 7 10 15 20 25 30 35 40 45 50 55 60 65 70 75
Age group (years)
n=28 44 38 62 78 75 108 84 66 79 61 50 33 27 n=30 45 28 67 67 113 105 82 63 86 64 44 38 27
Figure 1: Systolic and diastolic blood pressures (BP) in 5-year age groups in a representative sample of the population of Noord
Limburg, Belgium
n=number of patients. Closed symbols show the mean of ten conventional blood pressure readings obtained at two visits by the study nurses in the
patients’ homes. Open symbols are mean daytime (10–20 h) ambulatory blood pressure values recorded every 20 min by oscillometric recorders.
1630 THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com
SEMINAR
predictive superiority of ambulatory over conventional

GLOSSARY
blood pressure. Additionally, a blunted fall in nocturnal
EPIGENETIC MECHANISM
blood pressure is a harbinger of an unfavourable outcome,
A term used to describe non-mutational occurences, such as DNA
irrespective of whether the decrease is assessed as a
methylation and histone modification, which change the expression of a continuous18 or a dichotomous characteristic.19 In clinical
gene. Histones are proteins around which double-stranded DNA is coiled practice, the commonly used definition of white-coat
and make up the core of a nucleosome, the most fundamental unit of hypertension is raised clinic blood pressure in the
DNA packaging in the nucleus. presence of a normal daytime ambulatory blood
IMPRINTS pressure.20,21 Results of event-based studies16,22 have clearly
Genetic imprinting is any mechanism by which individual cells express shown that the risk of cardiovascular disease is lower in
the maternal or paternal allele of a gene, but not both. Although patients with white-coat hypertension than in those with
commonly used in relation to autosomal genes, X chromosome raised ambulatory blood pressure, even after controlling
inactivation is a form of imprinting.
for concomitant risk factors. When daytime ambulatory
PENETRANCE blood pressure was below 130 mm Hg systolic and
The extent to which a person carrying a defined allele has an altered 80 mm Hg diastolic, the incidence of cardiovascular
phenotype. disorders did not differ between normotensive people and
RECOMBINATION MAXIMA those with white-coat hypertension.16,20 The counterpart of
Recombination is the crossover of chromosome fragments between the white-coat hypertension is masked hypertension, a disorder
maternal and paternal homologues of each chromosome pair during the characterised by a normal conventional blood pressure
meiosis, the specialised cell division giving rise to sperm and egg cells. confirmed on repeated clinic visits, but a raised daytime
Recombination maximum refers to the location along the chromosome
ambulatory blood pressure.23,24 Preliminary observations
at which recombination is most likely to occur.
suggest that this condition is associated with more target
SYNTENY organ damage than that noted in patients with sustained
The property of genes to be localised on the same chromosome across normotension.23,24
species. Conservation of synteny shows that a group of genes which is
Self-measurement of blood pressure at home is cheaper
on one chromosome in one species are similarly linked in a second
species. than ambulatory monitoring. To pass validation,14 monitors
for self-measurement must conform to the same quality
standards as devices for ambulatory monitoring. Use of
high-to-normal blood pressure, as defined in panel 1, is wrist devices is not recommended.14 To ensure a reliable
associated with an increased risk of cardiovascular disease6 report of home blood pressure readings as instructed by a
and incidence of hypertension.11 Compared with optimum professional, values must be downloaded from the memory
blood pressure, high-normal blood pressure was of a device or printed. If applied correctly, self-
associated with a risk-factor-adjusted hazard ratio for measurement accomplishes several of the advantages of
cardiovascular disease of 2·5 in women and 1·6 in men.6 ambulatory monitoring, including the increased number of
Similarly, the incidence of hypertension rose stepwise readings, the absence of the white-coat syndrome, and
across the non-hypertensive blood pressure categories. (when automated devices are used) the absence of observer
Below age 65, the 4-year rates were 5·3% in patients with bias. Furthermore, self-measurement could increase
optimum blood pressure, 17·6% in those with normal compliance to prescribed drugs and reduce the number of
blood pressure, and 37·3% in those with high-normal clinic visits required for the diagnosis and the treatment of
blood pressure.11 Corresponding 4-year rates of hypertension.25 Diagnostic thresholds have been proposed
progression to hypertension in subjects of 65 years and (panel 1),26 but they have not yet been widely validated by
older were 16·0%, 25·5%, and 49·5%, respectively.11 prospective outcome studies.27
Conventional measurement remains the standard
Diagnosis method for assessment of blood pressure. In patients with
For the diagnosis of hypertension, doctors rely mainly on raised clinic blood pressure and either target organ damage
Riva-Rocci’s technique and the auscultation of the or a high cardiovascular risk profile, treatment can be
Korotkoff sounds. Raised clinic blood pressure readings started without confirmation of the increased clinic
have to be confirmed on at least two visits with intervals readings by automated measurement techniques. However,
dependent on the height of the blood pressure, presence when raised blood pressure is the only detectable
of target organ damage, and other cardiovascular risk abnormality or when patients with a normal clinic blood
factors.10,12,13 Nowadays, automated blood pressure pressure show unexplained target-organ damage, self-
measurement is increasingly used in clinical practice, measurement, ambulatory monitoring, or both must be
mainly for diagnosis of the white-coat syndrome, which used to exclude white-coat hypertension or masked
consists of a transient rise of a patient’s blood pressure in hypertension, respectively (figure 2). In the absence of
response to the medical environment or the observer other cardiovascular risk factors and signs of target organ
recording the blood pressure. The accuracy of devices for damage, treatment of patients with white-coat
measurement of blood pressure should be assessed in hypertension can be restricted to lifestyle measures and
validation studies according to internationally recognised yearly follow-up of ambulatory blood pressure.28
protocols14 and published in peer-reviewed journals.
Diagnostic thresholds are available for different types of Pathophysiology
automated blood pressure measurement in adults Sodium and fluid balance and vasomotor tone are
(panel 1), whereas those for children and adolescents are cornerstones in blood pressure regulation. Both
still under discussion.15 mechanisms are affected by numerous genetic and
Ambulatory monitoring substantially refines the risk environmental factors, and are controlled by hormonal,
stratification provided by conventional sphygmomanom- nervous system, paracrine, and intracellular feedback
etry, both in hypertensive patients16 and in the general loops. The interactions between these factors change with
population.17 The greater number of measurements, the age, and account for the heterogeneous pattern of the
absence of digit preference and observer bias, and the haemodynamic alterations that lead to and sustain high
reduction of the white-coat effect contribute to the blood pressure throughout life.
SEMINAR
White-coat hypertension Masked hypertension exchange and, through calcium-

(Isolated clinic hypertension) (Isolated ambulatory
dependent pathways, stimulate
hypertension) excitation-contraction coupling and
the expression of growth-related
genes.34,38 At very low concentrations
Persistently raised Persistently normal within the nanomolar range,
clinic blood pressure clinic blood pressure endogenous ouabain may increase
the size of the membrane pool of
Yes active sodium pumps43 and by this or
Target organ damage? Target organ damage? other unknown mechanisms lead to
renal sodium conservation rather than
No Yes loss of salt.39
High High
Home Start 24-h ambulatory Stimulation of the renal sympathetic
Low
treatment blood pressure nerves and activation of the renin-
angiotensin system promote sodium
24-h ambulatory High and fluid retention. Interactions
blood pressure between both pathways of sodium
handling occur intrarenally as well as
Low extrarenally. Circulating angiotensin II
Continue to monitor Continue to monitor facilitates the presynaptic release of
clinic and home clinic and ambulatory noradrenaline.40 It can also directly
blood pressure blood pressure increase sympathetic outflow from the
subfornical organ and the area
Figure 2: Guidelines for assessment of patients by use of clinic, home, and ambulatory postrema, two specialised areas within
monitoring of blood pressure the central nervous system that lack a
Modified from reference 21. For definitions of normotension and hypertension, see panel 1. blood-brain barrier.44 Furthermore,
angiotensin II itself acts as a
Sodium and fluid balance peptidergic neurotransmitter in the brain.45 Angiotensin II,
According to pioneering research29 and subsequent originating from neurons in the paraventricular nucleus,
evidence,30 the kidneys play a central part in the attenuates the reflex modulation of sympathetic outflow
pathophysiology of essential hypertension. Blood pressure from the brain and activates sympathetic preganglionic
starts to rise when the kidney requires a higher than usual neurons. These central effects of angiotensin II are greatest
blood pressure to maintain extracellular fluid volume during a low sodium diet (high renin activity), least during
within normal limits.29 Models of essential hypertension in high sodium intake (low renin activity), and tonic during
rats share the characteristic that renal sodium excretion is normal sodium diet.40
impaired at any degree of blood pressure.31 In rats32 and
man,33 transplantation of a kidney from a normotensive Microvascular and macrovascular mechanisms
donor reduces the blood pressure. Such findings32,33 do not Increased peripheral arterial resistance is the hallmark of
suggest that the disturbance causing essential essential hypertension. The active component of arteriolar
hypertension only affects the kidneys. Indeed, essential resistance depends on the contraction of vascular smooth
hypertension is characterised by generalised membrane muscle cells. Structural changes in the wall-to-lumen ratio
abnormalities,34 which could affect the function of many are termed vascular remodelling.46 Histopathological
organs in various ways. studies of gluteal arterioles mounted on wire myographs
The central role of the kidney in the pathogenesis of have shown that resistance vessels of hypertensive patients
hypertension should be differentiated from salt sensitivity. have a reduced lumen, an increased media-to-lumen ratio,
Secondary forms of hypertension, such as but a normal medial cross-sectional area.46 Experimental
pheochromocytoma or hyperaldosteronism, can also be evidence favours the notion that these morphological
associated with a reduced ability of the kidneys to excrete alterations arise as an adaptation to the increased blood
a sodium load. In such cases, removal of the primary pressure through changes in the neurohumoral milieu,
cause of hypertension corrects the enhanced renal sodium and that they amplify rather than cause increase of blood
reabsorption. In genetic forms of hypertension, salt- pressure.47 Vascular hypertrophy associated with
sensitivity may result from various mutations affecting hypertension can also lead to closure of small vessels.48
cytoskeleton proteins,35,36 ion transporters,34 or endocrine Vascular rarefaction could therefore contribute to the
factors37,38 that control renal sodium handling. In other increased vascular resistance in long-standing
forms of hypertension, salt-sensitivity originates in an hypertension.
imbalance between the hormonal,39 nervous,40 or Isolated systolic hypertension in older patients is a
haemodynamic29 regulations that affect sodium balance separate disease entity due to stiffening of the large
through changes in glomerular filtration or tubular arteries with advancing age. Aortic pulse wave velocity, an
reabsorption. index of arterial stiffness, doubles between 15 and
The hormone ouabain is released endogenously from 70 years of age.49 The arterial pressure wave consists of a
the adrenal glands and possibly from the midbrain41 in forward component generated by the heart and reflected
response to hypoxia41 or expansion of the extracellular waves returning to the heart from peripheral sites.4,49 In
fluid volume induced by aldosterone.42 Evidence suggests healthy young adults, the reflected waves coincide with
that, dependent on its concentration, this hormone diastole, raise diastolic pressure, and boost coronary
behaves as a versatile modulator of the ubiquitously perfusion. With arterial stiffening, which arises with
expressed sodium pump.39 In renal tubular cells, ageing or in advanced hypertension, the reflected waves
inhibition of Na/K ATPase activity by ouabain move faster, reach the proximal aorta during systole, and
promotes natriuresis. In cardiac and vascular myocytes, cause an augmentation of late systolic pressure, whereas
this process could slow the sarcolemmal Na/Ca2 diastolic pressure decreases.4,49 Lowered diastolic pressure
SEMINAR
can impair coronary blood flow and predispose to coefficients between relatives, usually in the range
myocardial ischaemia. Increased systolic pressure 0·1–0·3. Parent-offspring correlations tend to be smaller
augments cardiac work and can lead to heart failure. The than those among siblings. Heritability estimates,
age-related changes in the elastic properties of the large generally based on complex biometrical assumptions and
arteries and in the wave reflections also account for the Mendelian mechanisms of inheritance, cluster around
greater brachial artery pressure than central aortic 20% in family studies, but in twin studies they vary
pressure in young patients, whereas in the elderly or in around 60%.50
patients with end-stage renal disease4 both values tend to
be similar. Monogenic forms of blood pressure dysregulation
The last decade witnessed tremendous progress in high-
Genetics of human hypertension throughput genomics and proteomics, which allow many
More than 40 years ago, at the time of the controversy samples to be processed in a short time, as well as in cell
between Sir George Pickering and Robert Platt, and molecular biology. Technological advances led to the
researchers had already noticed that hypertension runs in discovery of 17 human genes (panel 2)52 that cause
families. Population-based studies show correlation Mendelian forms of either hypertension or hypotension.
Panel 2: Mendelian forms of blood pressure dysregulation
Syndrome* Phenotype† Mutation‡ Mechanism

Glucocorticoid remediable HT, serum K↓, alkalosis, PRA↓, Chimerical gene containing Chimerical enzyme is
aldosteronism (GRA) aldosterone suppressible by promoter area of AS and regulated by ACTH
dexamethasone coding region of 11H
(dominant)
Apparent mineralocorticoid HT, aldosterone↓, serum K↓, Absence of 11HSD Impaired conversion of
excess (AME) alkalosis, PRA↓, suppressible by (recessive) cortisol (activates MR) to
spironolactone cortisone (inactive at MR)
Hypertension exacerbated by HT accelerated in pregnancy, PRA↓ Missense mutation in MR Steroids without 21-hydroxyl
pregnancy37 receptor (dominant) group (progesterone) and
spironolactone stimulate
mutant MR receptor
Dominant pseudohypo- BP↓, aldosterone↑, neonatal salt Mutant MR (usually dominant, Early in life, normal salt
aldosteronism type 1 wasting, serum K↑, acidosis, but recessive variant homoeostasis requires two
(PHA 1)51 renal phenotype disappears in identified) normal copies of MR
adulthood
Recessive pseudohypo- BP↓, aldosterone↑, neonatal salt Mutated , , or subunit Loss of function of ENaC
aldosteronism type 1 wasting, serum K↑, acidosis, of ENaC (recessive)
(PHA 1) phenotype does not improve with
ageing, impaired clearance of lung
water (respiratory failure)
Pseudohypoaldosteronism HT, serum K↑, PRA↓, normal Mutations in at least one of Volume-expanded HT,
type 2 (PHA 2) renal function 3 genes mapped to 1q31–42, probably due increased renal
12p13, and 17p11–q21 tubular sodium reabsorption
(dominant)
Liddle syndrome Early onset HT, aldosterone↓, Mutations of or subunit of Increased ENaC activity due
serum K↓, alkalosis, PRA↓ ENaC (dominant) to reduced ENaC clearance
Hypertension with Severe HT, abnormal skeletal Mutations mapped to Unknown
brachydactyly development of hand, stroke 12p11.2–12.2 (dominant)
Peroxisome proliferator- HT associated with insulin Missense mutation (dominant) Desensitisation of PPAR
activated receptor resistance or diabetes, responsive receptor
gamma (PPAR) to thiazolidinediones
Defective aldosterone BP↓, aldosterone↓, Na1loss, Deficient AS or 21 hydroxylase Aldosterone deficiency
synthesis Kretention (recessive)
Gitelman’s syndrome BP↓, serum Mg2↓, serum K↓, Mutation of the thiazide- Loss of function
alkalosis, hypocalciuria, PRA↑, sensitive NaCl cotransporter
aldosterone↑ in the distal collecting duct
(recessive)
Bartter’s syndrome BP↓, serum K↓, alkalosis, Mutation in ion transporters Loss of function
hypercalciuria, PRA↑, aldosterone↑ in thick ascending limb
of Henle: Na-K-2Cl,
ATP-sensitive K channel, or
Cl channel (recessive)
AS=aldosterone synthase. BP=blood pressure. ENaC=epithelial sodium channel. 11H=11-hydroxylase. 11HSD=11-hydroxysteroid dehydrogenase.
HT=hypertension. MR=mineralocorticoid receptor. PRA=plasma renin activity. *Name of the syndrome and commonly used acronym. Original articles are
listed in reference 52. †Main characteristics of the phenotype. ‡Change in the gene or gene product. Dominant or recessive refer to the pattern of
autosomal inheritance.
SEMINAR
Phenotype Effect A second layer of complexity in the study of blood

pressure as a quantitative trait originates from the
Nucleus Multiple genes inconsistency of the relationship between phenotype and
genotype. Many genes might influence the same
phenotype, or a sole mutation could be associated with
Proteins and grossly discordant phenotypes.64 Even in monogenic
subcellular IP disorders with typical Mendelian inheritance (panel 2),
organelles PENETRANCE may vary according to race,55 age,51,55 dietary
salt intake,51 hormonal milieu,37,38 or just from one case to
Host factors another.64 Mendelian principles or the biometrical
Cell IP (race, sex, age, etc) assumptions underlying the decomposition of variance
into genetic, environmental, and random components,
might not apply to multigenic quantitative traits. Indeed,
Tissue IP cardiovascular phenotypes are affected by distinct
maternal and paternal genomic IMPRINTS that result in a
divergent expression of parental alleles during fetal
Whole BP Environment development and postnatal growth into adulthood.65
organism HT Lifestyle Offspring inherit their mitochondrial DNA mainly66 but
Figure 3: Schematic representation of blood pressure as a not exclusively67 from their mother. Maternal and paternal
complex multigenic trait, affected by host and environmental chromosomes show differences in location of
factors and feedback control RECOMBINATION MAXIMA.68 The intrauterine environment
IP=intermediate phenotypes. BP=blood pressure. HT=hypertension. might affect the occurrence of cardiovascular disease later
Curved arrows represent feedback loops. in life and is largely controlled by genetic and
environmental factors linked to the mother.69 Finally,
However, monogenic disorders of blood pressure epigenetic mechanisms may lead to transdifferentiation,
regulation are rare and do not explain blood pressure whereby specialised cells can undergo profound changes
variability in the population at large.53 in their function.70
How, then, can researchers cope with the complexity of
Blood pressure as a polygenic quantitative trait human essential hypertension? Some experts favour the
Until now, geneticists have failed to identify common whole genome approach71–74 and exploit SYNTENY between
genes with large effects on human hypertension. It is species75 in the search for major genes that could lead to
conceivable that such genes do not exist and that blood hypertension. Inbred rats and genetically-engineered
pressure is dependent on a mosaic of many loci, each mice, in which gene activities have been specifically
with a small influence or with a contribution differing manipulated, produced new insights in the long-term
according to sex,54 race,55,56 age,51,55 or lifestyle. However, regulation of blood pressure.31,72 However, these rodent
many studies57 have limitations such that the existence of models31,72 do not stand comparison with the complexity
major genes controlling blood pressure cannot yet be and heterogeneous nature of the human disease. Other
completely ruled out. Lack of standardisation and investigators verified prespecified hypotheses about
arbitrary dichotomisation of a continuous and variable known candidate genes,76 such as those listed in
phenotype, inappropriate selection of cases and controls, panel 33,57,71,72,74,77-91 and tried to reconstruct the
population admixture and stratification, insufficient pathogenesis of hypertension from cells up to the systemic
sample size, and failure to account for confounders, level. Under controlled laboratory conditions, they
environmental factors, or EPIGENETIC MECHANISMS, measured intermediate phenotypes less distant from the
remain key obstacles to substantial progress. DNA than blood pressure, such as modulation status.92
Other reasons could also account for the shortfall, but Non-modulators show blunted renovascular and adrenal
they are generally underappreciated. First, in most responses to infused angiotensin II in sodium repleted and
people, blood pressure behaves as an age-related sodium depleted conditions, respectively.92 Selective
quantitative trait (figure 1). Advancing age increases salt blockade of molecular mechanisms in pharmacogenomic
sensitivity,58 steepens the relationship between blood experiments may constitute the final leg of the long
pressure and exchangeable body sodium,59 decreases the journey from bench to bedside.93 For instance, in patients
gain of the baroreceptor reflex,60 reduces renal with a genetic predisposition to salt retention, diuretics
perfusion,61 and compromises the buffering effects of the may lower blood pressure more than other treatments.93
large arteries on both systolic and diastolic blood However, when used in isolation, the pharmacogenomic
pressure.62 Throughout life, genetically determined host approach also has weakness, because a drug rarely
factors continuously interact with environmental possesses the necessary selectivity. Moreover,
influences, including lifestyle (figure 3). Any resulting interindividual differences in pharmacokinetics could alter
change in blood pressure is initially counteracted by self- drug effects irrespective of specific interference with
organising homoeostatic mechanisms, which encompass mechanisms that regulate blood pressure.94
intracellular signalling, metabolic and hormonal The discovery of the role of adducin in human
regulation at cell and tissue levels, as well as systemic hypertension illustrates the potential of multidisciplinary
feedback loops involving the whole body. For instance, research along the lines of a predefined pathophysiological
acutely induced hypertension causes a rapid shift in hypothesis. Adducin is a cytoskeleton protein.81,82
sodium pump activity from proximal to distal sites of the Investigations in rats,81,95 in-vitro transfection studies,35
nephron.63 Since findings obtained under controlled interventions in never-treated hypertensive patients,36 and
experimental conditions or in defined populations cannot epidemiological studies96,97 have shown a logical sequence
be easily generalised, this innate plasticity of living of events leading from a point mutation in the subunit95
organisms (figure 3) should be incorporated into the to a cellular dysfunction characterised by higher activity of
search for genes that may cause essential hypertension in the sodium pump,35 hence increased tubular sodium
man. reabsorption in the kidney,36 and ultimately
SEMINAR
hypertension.96 In caucasian people, the mutated 70 Hypertension 900 Femoral intima-media

-adducin allele and the deletion polymorphism of the thickness
ACE gene jointly predicted the incidence of hypertension 60 DD (n=63) 850
Incidence per 100 patients

(figure 4).96 In cross-sectional analyses of the same ID+II (n=195)
population, these two polymorphisms combined were 50
associated with raised serum creatinine concentration97, 800
increased femoral intima-media thickness,98 and 24-h 40 +59%
proteinuria97 (figure 4). Such effects of mutated adducin
µm
p=0·004 750
are in keeping with renal cross-transplantation
30
experiments.32,33 The adducin hypothesis was further
substantiated by the finding that the blood pressure was 700
20
lowered by a specific inhibitor of the sodium pump99 and
by the observation that hypertensive carriers of the 650 p=0·03
mutated -adducin have reduced cardiovascular 10
(vs DD)
complications if they are treated with diuretics instead of
drugs that do not antagonise the enhanced tubular 0 600
sodium reabsorption.100 4 6 8 10 12 n=44 79 44
Years of follow-up II ID DD
Intervention through lifestyle
In chimpanzees given a vegetarian diet with very low
sodium and high potassium content, salt repletion Proteinuria
95 Serum creatinine 0·12
(10–15 g per day for 20 months) caused a rise in blood
pressure by 33 mm Hg systolic and 10 mm Hg diastolic.101 94
Intervention studies in man102 produced the most 0·11
93
convincing evidence for the role of salt in hypertension. A
meta-analysis of 56 trials accounted for measurement 92
0·10
error of urinary sodium excretion. For a reduction of the
91
µmol /L
daily sodium excretion by 100 mmol (about 6 g of salt),
g/day
the decline in blood pressure in hypertensive patients 90 0·09
averaged 3·7 mm Hg (95% CI 2·4–5·0) systolic and 89
0·9 mm Hg (–0·1 to 1·8) diastolic.102 The corresponding 0·08
decreases in normotensive subjects were small: 88 p<0·008
p=0·02
1·0 mm Hg (95% CI 0·5–1·6) and 0·1 mm Hg ( –0·3 to (vs ID or DD)
87 (vs DD)
0·5), respectively. In the Dietary Approaches to Stop 0·07
Hypertension (DASH) trial,103 participants were fed meals 86
with varying salt levels for more than 4 weeks. The DASH 85 0·06
diet was rich in fresh fruits, vegetables, and low-fat diary
products. For both the DASH and traditional diets, the n=139 299 155 n=51 117 53
lower the salt intake, the lower was the blood pressure.103 II ID DD II ID DD
In line with the concept of pressure-natriuresis,29 some
studies demonstrated the restoration of a dipping diurnal Figure 4: Association between a complex phenotype and the
blood pressure profile in non-dipping hypertensive ACE I/D polymorphisms in carriers of the mutated -adducin
patients given a low-salt diet.104 However, high sodium Trp allele
intake105-107 associated or not with sodium sensitivity,105,107 Individuals were recruited from a Flemish population in Belgium. The
did not uniformly predict a worse cardiovascular outcome complex phenotype consisted of hypertension, intima-media thickness of
the femoral artery, serum creatinine concentration, and proteinuria. The
in prospective studies. Furthermore, sodium restriction total number of patients investigated for each phenotype amounted to
does not normalise peripheral vascular resistance, the 678,96 380,98 1454,97 and 556,97 respectively. The corresponding
main haemodynamic disturbance in essential hyper- associations in homozygous carriers of the wild-type -adducin were not
tension.108 significant.
Stopping excessive alcohol consumption (>30 mL
ethanol per day)109 and restriction of caloric intake110 are by pressure. However, the main goal of antihypertensive
far the most effective lifestyle measures that consistently treatment is not to reduce blood pressure per se, but to
reduce blood pressure. In an overview of intervention prevent the cardiovascular and renal complications
studies, a 1 kg loss of weight entailed an average blood associated with raised blood pressure, extend longevity,
pressure decrease by 1·6 mm Hg systolic and 1·3 mm Hg and improve quality of life. Several quantitative
diastolic.110 Other lifestyle measures that have the potential overviews2,113–115 provide a detailed account of the outcome
to slightly diminish blood pressure are regular dynamic trials in hypertension, including study design, study
exercise (30–45 min for at least 4 days per week)111 and quality, and the effects of treatments on primary and
abstaining from smoking.112 These lifestyle measures are secondary endpoints.
recommendable because they reduce not only blood
pressure but also cardiovascular risk. Primary prevention
Placebo-controlled trials of antihypertensive drug
Antihypertensive drug treatment treatment in middle-aged and older hypertensive patients
Agencies currently approve new drugs for with predominantly diastolic hypertension showed that a
antihypertensive treatment on the basis of the treatment’s 5–6 mm Hg mean decline in diastolic pressure sustained
potential to decrease blood pressure as an intermediate over 5 years reduced incidence of stroke by nearly 40%
endpoint. Despite substantial evidence of the risk of and that of coronary events by 15%.113 In older patients
isolated systolic hypertension in older people,2 regulations with isolated systolic hypertension, treatment diminished
require lowering of both systolic and diastolic blood the stroke rate by one third and the incidence of coronary
SEMINAR
Panel 3: Putative candidate genes or quantitative trait loci implicated in blood pressure regulation
Receptors Cellular or paracrine agents Hormones or vasoactive Other proteins or QTLs
substances
Angiotensin receptors 1b and , , subunits of adducin81,82 Renin, angiotensinogen, angiotensin- SA locus78
257,72 converting enzyme57
Atrial natriuretic peptide 1, 2, 1 isomers of NaK Atrial and brain natriuretic peptides QTLs associated with X- and
receptor/guanylyl cyclase A72 ATPase, Na,K,2Cl-cotransporter83 Y-chromosomes72
Glucocorticoid receptor77 , , subunits of epithelial 11-hydroxylase, aldosterone QTL on human 12q21.3374

sodium channel85 synthase
Dopamine receptors 1, 2 and Renal epithelial potassium Endothelin 2 and 372 QTLs associated with Lewis
372,74 channel72 blood group and complement
C3F89
1b, 2, and 2 adrenergic 3 subunit of G-protein79 Endothelial nitric oxide synthase84 QTL associated with human
receptor72 pancreatic phospholipase A288
Insulin receptor91 Calmodulin-dependent protein Prostacyclin synthase87 Neuropeptide Y72
kinase II72
Leptin receptor71 Adipsin71 Growth hormone86 Tyrosine hydroxylase80
Interleukin 672 Corticotropin releasing hormone71 Lipoprotein lipase90
Transforming growth factor 74
QTL=quantitative trait locus. Candidate genes were identified on the basis of rare Mendelian diseases (panel 2), genome scans, positional mapping, or
potential functional relevance.
events, including sudden death, by nearly 20%.2 Nifedipine Trial on Antiatherosclerotic Therapy, short-
Furthermore, antihypertensive treatment substantially acting nifedipine (n=173) compared with placebo
reduced the risk of heart failure, although estimates of (n=175) reduced the number of new coronary lesions by
benefit varied across trials because of differences in the 28%, but the drug was associated with higher all-cause
clinical criteria used for diagnosis. (14 vs 2) and cardiac mortality (10 vs 2), whereas the
In the Systolic Hypertension in Europe (Syst-Eur) incidence of non-fatal cardiac events was similar in both
trial,116 dementia was a pre-specified secondary endpoint. groups (52 vs 44).134
After a median follow-up of 3·9 years, treatment starting
with the dihydropyridine calcium-channel blocker Comparative trials
nitrendipine reduced the rate of degenerative dementia by In nine trials, 62 605 hypertensive patients were ran-
55% (p<0·001).116 In view of the null results observed in domised to initial treatment with old drugs (diuretics and
other placebo-controlled studies testing thiazides,117,118 blockers), or new agents (calcium-channel blockers and
blockers,117,118 or monotherapy with the ACE inhibitor converting-enzyme inhibitors). Compared with old drugs,
perindopril,119 the Syst-Eur findings might be due to new agents offered similar overall cardiovascular
chance rather than to blood pressure lowering or the protection, but calcium-channel blockers provided more
inhibition of calcium influx into ischaemic brain reduction in the risk of stroke (13·5%, 95% CI
neurons.120 Thus, the concept that antihypertensive 1·3–24·2%, p=0·03) and less reduction in the risk of
treatment with long-acting dihydropyridines might myocardial infarction (19·2%, 3·5–37·3%, p=0·01).114
protect against dementia needs further testing in These cause-specific outcome results confirm findings of
controlled clinical trials. other investigators,135 but have wide confidence intervals,
and therefore must be interpreted with caution.
Secondary prevention The researchers of the Losartan Intervention for
Several trials119,121-125 have tested the hypothesis that Endpoint Reduction in Hypertension Study (LIFE)136
inhibitors of the renin-angiotensin system might be more reported that first-line treatment with losartan, compared
effective than placebo in the secondary prevention of with atenolol, improved outcome over and beyond blood
stroke and the cardiovascular-renal complications of pressure control. They measured achieved blood pressure
hypertension. These drugs diminished the frequency of at the end of follow-up (mean 4·8 years) or just before an
cardiovascular events123,124 and stroke recurrence.119 In event. This definition did not account for the differences
diabetic patients with normoalbuminuria123 or in systolic pressure (higher on atenolol), diastolic pressure
microalbuminuria,125 they also decreased the incidence of (lower on atenolol), or pulse pressure (higher on
overt nephropathy, but they did not reduce the rate of atenolol), which arose during the first year of follow-up.
progression of coronary122 or carotid121 atherosclerosis. In addition, in older patients such as those enrolled in the
Furthermore, in patients with overt nephropathy due to LIFE study (age range 55–80 years, mean age 66·9 years),
diabetes126,127 or hypertension,128 ACE inhibitors128 or blockers improve outcome less than diuretics.137
angiotensin receptor blockers126,127 were more effective The Antihypertensive and Lipid-Lowering Treatment
than conventional therapy126 or amlodipine127 in to Prevent Heart Attack Trial (ALLHAT)138,139 had 42 424
postponing a doubling of the serum creatinine participants aged 55 years or older with hypertension and
concentration or preventing end-stage renal disease. at least one other cardiovascular risk factor. They were
However, in line with Fleckenstein’s investigations in randomised to first-line antihypertensive therapy
animals,129 results of several trials have shown that long- with chlorthalidone (12·5 to –25·0 mg/day, n=15 255),
acting calcium-channel blockers compared with amlodipine (2·5–10·0 mg/day, n=9067), lisinopril
placebo,130 diuretics131,132 or atenolol133 slowed the (10–40 mg/day, n=9048), or doxazosin (2–8 mg/day,
progression of carotid atherosclerosis. In the International n=9054) with an intended follow-up of 4–8 years. The
SEMINAR
Group Relative risk (95%) versus chlorthalidone

Doxazosin139 Amlodipine138 Lisinopril138
Outcome
CHD* All 1·03 (0·90–1·17) 0·98 (0·90–1·07) 0·99 (0·91–1·08)
Combined CHD† All 1·10 (1·00–1·12) 1·00 (0·94–1·07) 1·05 (0·98–1·11)
Total mortality All 1·03 (0·90–1·15) 0·96 (0·89–1·02) 1·00 (0·94–1·08)
Non-CV mortality All .. 0·88 (0·79–0·97) 0·93 (0·84–1·03)
Combined CVD‡ All 1·25 (1·17–1·13) 1·04 (0·99–1·09) 1·10 (1·05–1·16)
65 years 1·29 (1·20–1·40) 1·05 (0·99–1·12) 1·13 (1·06–1·20)
Female .. 1·04 (0·96–1·13) 1·12 (1·03–1·21)
Black 1·40 (1·25–1·57) 1·06 (0·96–1·16) 1·19 (1·09–1·30)
Diabetic 1·24 (1·12–1·38) 1·06 (0·98–1·15) 1·08 (1·00–1·17)
Stroke All 1·19 (1·01–1·40) 0·93 (0·82–1·06) 1·15 (1·02–1·30)
65 years .. 0·93 (0·81–1·08) 1·13 (0·98–1·30)
Female .. 0·84 (0·69–1·03) 1·22 (1·01–1·46)
Black .. 0·93 (0·76–1·14) 1·40 (1·17–1·68)
Diabetic .. 0·90 (0·75–1·08) 1·07 (0·90–1·28)
Heart failure All 2·04 (1·79–2·32) 1·38 (1·25–1·52) 1·19 (1·07–1·31)
65 years 2·07 (1·78–2·41) 1·33 (1·18–1·49) 1·20 (1·06–1·35)
Female .. 1·33 (1·14–1·55) 1·23 (1·05–1·43)
Black 2·18 (1·73–2·74) 1·47 (1·24–1·74) 1·32 (1·11–1·58)
Diabetic 2·14 (1·76–2·58) 1·42 (1·23–1·64) 1·22 (1·05–1·42)
ESRD All .. 1·12 (0·89–1·40) 1·11 (0·88–1·38)
Main outcome results of the ALLHAT trial138,139 in all patients and prespecified subgroups
CHD=coronary heart disease. Non-CV mortality=non-cardiovascular mortality. CVD=cardiovascular disease. ESRD=end-stage renal disease. *Primary endpoint
including coronary mortality and non-fatal myocardial infarction. †Combined CHD includes coronary mortality, non-fatal myocardial infarction, coronary
revascularisation, and hospitalised angina pectoris. ‡Combined CVD consists of coronary mortality, non-fatal myocardial infarction, coronary revascularisation,
hospitalised or treated angina pectoris, stroke, hospitalised or treated congestive heart failure, and revascularisation for peripheral artery disease.
primary outcome, a composite of coronary mortality and complications of raised blood pressure. Accordingly, the
non-fatal myocardial infarction, occurred in 3321 need to start treatment increases in the presence of other
patients.138,139 Because of the twofold higher risk of heart cardiovascular risk factors or when absolute risk reaches a
failure on doxazosin compared with chlorthalidone, the specified threshold (for example in the British population,
doxazosin arm was stopped prematurely after a median a 10-year risk of coronary heart disease of 15% or
follow-up of 3·3 years.139 Follow-up of the other groups greater12).
lasted an average of 4·9 years.138 The key finding was that On the basis of evidence from trials, most10,12,13 but not
there were no differences between randomised patients in all guidelines10 suggest that low-dose thiazides might be
the primary outcome and total mortality. Compared with the most cost-effective way to start pharmacological
chlorthalidone, treatment starting with amlodipine was treatment in most patients. However, for each class of
associated with a higher risk of heart failure (table). antihypertensive drugs, compelling indications or
Furthermore, heart failure, stroke, and combined contraindications exist.10,12,13 For instance, blockers or
cardiovascular disease arose more frequently in patients calcium-channel blockers can be used in patients with
allocated doxazosin or lisinopril than in those of the angina pectoris. Stable heart failure is an indication for
chlorthalidone group (table). thiazides, aldosterone receptor blockers,140 blockers,141 or
Interpretation of the ALLHAT results is difficult, ACE inhibitors,124,142 but not for angiotensin receptor
because at randomisation 90% of the patients were blockers.143 A history of myocardial infarction favours the
already on antihypertensive treatment, most often use of blockers144 or ACE inhibitors.124,142 Renal
diuretics. Thus, this trial tested continuation of a diuretic impairment, microalbuminuria, or proteinuria is an
versus switching drug classes. Patients on diuretics with indication for ACE inhibitors123,128 or angiotensin receptor
latent or compensated heart failure were deprived of their blockers.125-128 Systolic hypertension warrants the use of
treatment when they were not randomised to thiazides117 or long-acting dihydropyridines.115 In black
chlorthalidone. Moreover, the achieved systolic pressure people, hypertension responds better to thiazides or
was higher with doxazosin (2·0 mm Hg),139 amlodipine calcium-channel blockers than to inhibitors of the renin
(1·1 mm Hg),138 and lisinopril (2·3 mm Hg) than with system, in terms of both blood pressure reduction138,145 and
chlorthalidone.138,139 Presumably, these factors explain why prevention of complications.138,142 In the absence of renal
the Kaplan-Meier curves started to diverge immediately impairment at the initiation of antihypertensive
after randomisation for heart failure and approximately treatment, all major drug classes equally prevent end-
6 months later also for stroke.115 Furthermore, the stage renal disease.138
sympatholytic agents used for step-up treatment (atenolol, The discussion about which drug class is better suited
clonidine, or reserpine, at the physician’s discretion) led to start antihypertensive therapy is largely obsolete. In
to a somewhat artificial treatment regimen, which does most patients, several drug classes and combinations need
not accord with modern clinical practice.138 to be rotated to optimise treatment at acceptable
Notwithstanding these limitations, ALLHAT stands out tolerance. The blood-pressure lowering activities of ACE
as the largest double-blind trial ever undertaken in inhibitors and blockers are additive to those of thiazides
hypertensive patients. The study was managed and and calcium-channel blockers, and vice-versa.146 Patients
analysed independent of the pharmaceutical industry. younger than 50 years may be started on ACE inhibitors
or blockers and switched to thiazides or calcium-
Guidelines for antihypertensive drug therapy channel blockers if blood pressure remains uncontrolled,
In view of the evidence from clinical trials, guidelines for whereas the reverse order can be used in those older than
the treatment of hypertension10,12,13 are under revision. 50 years.146
However, most experts recommend an integrated The target of antihypertensive treatment is to achieve
approach of risk management to prevent the normal levels of systolic and diastolic blood pressure as
SEMINAR
defined in panel 1. In young people and patients with pressure on the risk of cardiovascular disease. N Engl J Med 2001;
diabetes mellitus, previous cardiovascular disorders, 345: 1291–97.
multiple risk factors, or renal insufficiency, blood pressure 7 Thomas F, Bean K, Guize L, Quentzel S, Argyriadis P, Benetos A.
Combined effects of systolic blood pressure and serum cholesterol
must be lowered to within the optimum or normal range, on cardiovascular mortality in young (<55 years) men and women.
if possible. To achieve blood pressure control, more than Eur Heart J 2002; 23: 528–35.
two-thirds of patients need a combination of two or more 8 Wu K, Xie L, Chen D, Chen J. The natural history of borderline
drugs.138 A meta-regression analysis115 included 149 407 hypertension in a Chinese population. J Hum Hypertens 1997; 11:
95–100.
patients randomised in 30 trials. In contrast to recent
9 Gillum RF. The epidemiology of cardiovascular disease in black
suggestions of benefit beyond blood pressure Americans. N Engl J Med 1996; 335: 1597–98.
lowering,124-127,136 this overview115 suggested that most of the 10 Guidelines Committee. 2003 European Society of Hypertension/
benefit of antihypertensive treatment could be explained European Society of Cardiology Guidelines for the Management of
by the decrease in blood pressure rather than by ancillary Arterial Hypertension. J Hypertens 2003 (in press).
drug properties, and therefore shows the need for tight 11 Vasan RS, Larson MG, Leip EP, Kannel WB, Levy D. Assessment
of frequency to progression to hypertension in non-hypertensive
blood pressure control. participants in the Framingham Heart Study: a cohort study. Lancet
2001; 358: 1682–86.
Conclusions 12 Ramsay L, Williams B, Johnston GD, et al. Guidelines for
The causes of essential hypertension are still uncertain. management of hypertension: report of the third working party
of the British Hypertension Society. J Hum Hypertens 1999; 13:
For now, with few exceptions, our therapeutic approach 569–92.
to essential hypertension and its cardiovascular 13 Hypertension Society of Southern Africa endorsed by the Medical
complications remains generic rather than specifically Association of South Africa and the Medical Research Council.
targeted. The notion that the discovery of major genes or Guidelines for the management of hypertension at primary health
interference with a sole pathophysiological mechanism care level. S Afr Med J 1995; 85: 1321–25.
14 O’Brien E, Pickering T, Asmar R, et al. Working Group on Blood
will substantially advance prevention and treatment is an Pressure Monitoring of the European Society of Hypertension
oversimplification that ignores the heterogeneous nature International Protocol for validation of blood pressure measuring
of this disorder. Integration of genetic, molecular, clinical, devices in adults. Blood Press Monit 2002; 7: 3–18.
and epidemiological research could disclose the way in 15 Sorof JM, Portman RJ. Ambulatory blood pressure monitoring in the
which genetic and environmental factors lead to different pediatric patient. J Pediatr 2000; 136: 578–86.
16 Verdecchia P, Schillaci G, Borgioni C, Ciucci A, Pede S, Porcellati
expression of proteins controlling the processes that cause C. Ambulatory pulse pressure. A potent predictor of total
hypertension. This integrated approach may identify cardiovascular risk in hypertension. Hypertension 1998; 32: 983–88.
subsets of patients in whom specific combinations of 17 Ohkubo T, Hozawa A, Nagai K, et al. Prediction of stroke by
genetic and environmental factors raise blood pressure, ambulatory blood pressure monitoring versus screening blood
and could lead to individualised treatment. Blind pressure measurements in a general population: the Ohasama study.
J Hypertens 2000; 18: 847–54.
treatment by trial and error could then change into 18 Staessen JA, Thijs L, Fagard R, et al. Predicting cardiovascular risk
comprehensive and specific intervention with the using conventional vs ambulatory blood pressure in older patients
pathophysiological processes at work in every patient. with systolic hypertension. JAMA 1999; 282: 539–46.
19 Kario K, Pickering TG, Matsuo T, Hoshide S, Schwartz JE,
Contributors Shimada K. Stroke prognosis and abnormal nocturnal blood
All authors conceived and wrote the seminar. pressure falls in older hypertensives. Hypertension 2001; 38:
852–57.
20 Verdecchia P, Staessen JA, White WB, Imai Y, O’Brien ET.
Conflict of interest statement Properly defining white coat hypertension. Eur Heart J 2002; 23:
JAS and WHB did ad-hoc consultancies for pharmaceutical companies 106–09.
with commercial interests in the cardiovascular field. During their
21 Pickering TG. Blood pressure measurement and detection of
lifetimes, they have received funding for studies, seminars, and travel from
hypertension. Lancet 1994; 344: 31–35.
such companies. GB is an adviser to the Prassis Sigma Tau Research
Institute (Milan, Italy). 22 Fagard RH, Staessen JA, Thijs L, et al. Response to antihypertensive
therapy in older patients with sustained and nonsustained systolic
hypertension. Circulation 2000; 102: 1139–44.
Acknowledgments 23 Sega R, Trocino G, Lanzarotti A, et al. Alterations of cardiac
JAS thanks Hilde Celis, Elly Den Hond, Tatiana Kuznetsova, structure in patients with isolated office, ambulatory, or home
Tim Nawrot, Agnieszka Olszanecka, Katarzyna Stolarz, Lutgarde Thijs, hypertension: data from the general population (Pressione Arteriose
and Valérie Tikhonoff. Research cited in this review was partly sponsored Monitorate E Loro Associazioni [PAMELA] Study). Circulation
by the European Union (contracts IC15-CT98-0329-EPOGH and 2002; 104: 1385–92.
QLG1-CT-2000-01137-EURNETGEN). JGW was funded by the
24 Liu JE, Roman MJ, Pini R, Schwartz JE, Pickering TG,
Bilaterale Scientific and Technological Collaboration between the
Devereux RB. Cardiac and arterial target organ damage in adults
People’s Republic of China and Flanders (project BIL02/10). The
with elevated ambulatory and normal office blood pressure. Ann
funding sources had no role in the writing of the article.
Intern Med 1999; 131: 564–72.
25 Chatellier G, Dutrey-Dupagne C, Vaur L, et al. Home self blood
pressure measurement in general practice. The SMART Study.
References
Am J Hypertens 1996; 9: 644–52.
1 Franklin SS, Larson MG, Khan SA, et al. Does the relation 26 Thijs L, Staessen JA, Celis H, et al. The international database of
of blood pressure to coronary heart disease change with aging? self-recorded blood pressures in normotensive and untreated
The Framingham Heart Study. Circulation 2001; 103: 1245–49. hypertensive subjects. Blood Press Monit 1999; 4: 77–86.
2 Staessen JA, Ga̧sowski J, Wang JG, et al. Risks of untreated and 27 Ohkubo T, Imai Y, Tsuji I, et al. Home blood pressure measurement
treated isolated systolic hypertension in the elderly: meta-analysis has a stronger predictive power for mortality than does screening
of outcome trials. Lancet 2000; 355: 865–72. blood pressure measurement: a population-based observation in
3 Mitchel GF, Moyé LA, Braunwald E, et al. Sphygmomanometrically Ohasama, Japan. J Hypertens 1998; 16: 971–75.
determined pulse pressure is a powerful independent predictor 28 Staessen JA, Byttebier G, Buntinx F, et al. Antihypertensive
of recurrent events after myocardial infarction in patients with treatment based on conventional or ambulatory blood pressure
impaired left ventricular function. Circulation 1997; 96: 4254–60. measurement. A randomized controlled trial. JAMA 1997; 278:
4 Safar ME, Blacher J, Pannier B, et al. Central pulse pressure 1065–72.
and mortality in end-stage renal disease. Hypertension 2002; 39: 29 Guyton AC. Long-term arterial pressure control: an analysis from
735–38. animal experiments and computer and graphic models. Am J Physiol
5 Staessen JA, Thijs L, O’Brien ET, et al. Ambulatory pulse pressure as 1990; 259: R865–77.
predictor of outcome in older patients with systolic hypertension. 30 Keller G, Zimmer G, Mall G, Ritz E, Amann K. Nephron number
Am J Hypertens 2002; 15 (part 1): 835–43. in patients with primary hypertension. N Engl J Med 2003; 348:
6 Vasan RS, Larson MG, Leip EP, et al. Impact of high-normal blood 101–08.
SEMINAR
31 Bianchi G, Ferrari P. Renal factors involved in the pathogenesis of 57 Wang JG, Staessen JA. Genetic polymorphisms in the renin-
genetic forms of hypertension. In: Sassard J, ed. Genetic angiotensin system: relevance for susceptibility to cardiovascular
Hypertension. Colloque INSERM, Montrouge, France: John Libbey disease. Eur J Pharmacol 2000; 410: 289–302.
Eurotext, 1992: 447–58. 58 Whelton PK, Appel LJ, Espeland MA, et al. Sodium reduction and
32 Rettig R, Folberth CG, Stauss H, et al. Hypertension in rats induced weight loss in the treatment of hypertension in older persons. A
by renal grafts from renovascular hypertensive donors. Hypertension randomized controlled trial of nonpharmacologic interventions in the
1990; 15: 429–35. elderly (TONE). JAMA 1998; 279: 839–46.
33 Guidi E, Menghetti D, Milani S, Montagnino G, Palazzi P, 59 Beretta-Piccoli C, Weidmann P, Brown JJ, Davies DL, Lever AF,
Bianchi G. Hypertension may be transplanted with the kidney in Robertson JIS. Body sodium and blood volume state in essential
humans: a long-term historical perspective follow-up of recipients hypertension: abnormal relation of exchangeable sodium to age
grafted with kidneys from donors with or without hypertension in and blood pressure in male patients. J Cardiovasc Pharmacol 1984;
their families. J Am Soc Nephrol 1996; 7: 1131–38. 6 (suppl 1): S134–42.
34 Orlov SN, Adragna NC, Adarichev VA, Hamet P. Genetic and 60 Mancia G, Grassi G, Giannattasio C, Seravalle G. Sympathetic
biochemical determinants of abnormal monovalent ion transport in activation in the pathogenesis of hypertension and progression of
primary hypertension. Am J Physiol 1999; 276: C511–36. organ damage. Hypertension 1999; 34 (part 2): 724–28.
35 Tripodi G, Valtorta F, Torielli L, et al. Hypertension-associated 61 Schmieder RE, Schächinger H, Messerli FH. Accelerated decline in
point mutations in the adducin alpha and beta subunits affect actin renal perfusion with aging in essential hypertension. Hypertension
cytoskeleton and ion transport. J Clin Invest 1996; 97: 2815–22. 1994; 23: 351–57.
36 Barlassina C, Schork NJ, Manuta P, et al. Synergistic effect of 62 Aviv A. Chronobiology versus biology. Telomeres, essential
-adducin and ACE genes causes blood pressure changes with body hypertension, and vascular aging. Hypertension 2002; 40: 229–32.
sodium and volume expansion. Kidney Int 2000; 57: 1083–90. 63 Magyar CE, Zhang Y, Holstein-Rathlou NH, McDonough AA.
37 Geller DS, Farhi A, Pinkerton N, et al. Activating mineralocorticoid Downstream shift in sodium pump activity along the nephron during
receptor mutation in hypertension exacerbated by pregnancy. Science acute hypertension. J Am Soc Nephrol 2001; 12: 2231–40.
2000; 289: 119–23. 64 Muntau AC, Roschinger W, Habich M, et al. Tetrahydrobiopterin as
38 Schoner W. Endogenous cardiac glycosides, a new class of steroid an alternative treatment for mild phenylketonuria. N Engl J Med
hormones. Eur J Biochem 2002; 269: 2440–48. 2002; 347: 2122–32.
39 Manunta P, Messaggio E, Ballabeni C, et al. Plasma ouabain-like 65 Young LE. Imprinting of genes and the Barker hypothesis. Twin Res
factor during acute and chronic changes in sodium balance in 2002; 4: 307–17.
essential hypertension. Hypertension 2001; 38: 198–203. 66 Morris AA, Lightowlers RN. Can paternal mtDNA be inherited?
40 DiBona GF. Nervous kidney. Interaction between renal sympathetic Lancet 2000; 355: 1290–91.
nerves and the renin-angiotensin system in the control of renal 67 Schwartz M, Vissing J. Paternal inheritance of mitochondrial DNA.
function. Hypertension 2000; 36: 1083–88. N Engl J Med 2002; 347: 576–80.
41 De Angelis C, Haupert GT Jr. Hypoxia triggers release of an 68 Kong A, Gudbjartsson DE, Sainz J, et al. A high-resolution
endogenous inhibitor of Na+-K+-ATPase from midbrain and adrenal. recombination map of the human genome. Nat Genet 2002; 31:
Am J Physiol 1998; 274: F182–88. 241–47.
42 Rossi G, Manunta P, Hamlyn JM, et al. Immunoreactive endogenous 69 Barker DJ, Clark PM. Fetal undernutrition and disease later in life.
ouabain in primary aldosteronism and essential hypertension: Rev Reprod 1997; 2: 105–12.
relationship with plasma renin, aldosterone and blood pressure levels. 70 Surani MZ. Reprogramming of genome function through epigenetic
J Hypertens 1995; 13: 1181–91. inheritance. Nature 2001; 414: 122–27.
43 Ferrari P, Ferrandi M, Torielli L, et al. Antihypertensive compounds 71 Rice T, Rankinen T, Province MA, et al. Genome-wide linkage
that modulate the Na-K pump. In: Jørgensen PL, Karlish SJD, analysis of systolic and diastolic blood pressure: the Québec Family
Maunsbach AB, eds. Na, K-ATPase and related cation pumps: Study. Circulation 2001; 102: 1956–63.
structure, function, and regulatory mechanisms. Ann NY Acad Sci 72 Rapp JP. Genetic analysis of inherited hypertension in the rat.
(in press). Physiol Rev 2000; 80: 135–72.
44 Fink GD. Long-term sympatho-excitatory effect of angiotensin II: a 73 Cooper RS, Luke A, Zhu X, et al. Genome scan among Nigerians
mechanism of spontaneous and renovascular hypertension. linking blood pressure to chromosomes 2, 3, and 19. Hypertension
Clin Exp Pharmacol Physiol 1997; 24: 91–95. 2002; 40: 629–33.
45 Ferguson AV, Washburn DL. Angiotensin II: a peptidergic 74 Rice T, Rankinen T, Chagnon YC, et al. Genomewide linkage scan
neurotransmitter in central autonomic pathways. Prog Neurobiol 1998; of resting blood pressure. HERITAGE Family Study. Hypertension
54: 169–92. 2002; 39: 1037–43.
46 Mulvany MJ. Vascular remodelling of resistance vessels: can we 75 Zimdahl H, Kreitler T, Gösele C, Ganten D, Hübner N. Conserved
define this? Cardiovasc Res 1999; 44: 9–13. synteny in rat and mouse for a blood pressure QTL on human
47 Kvist S, Mulvany MJ. Reduced medication and normalization of chromosome 17. Hypertension 2002; 39: 1050–52.
vascular structure, but continued hypertension in renovascular 76 Tabor HK, Risch NJ, Myers RM. Candidate-gene approaches for
patients after revascularization. Cardiovasc Res 2003; 52: 136–42. studying complex genetic traits: practical considerations. Nat Rev
48 Serné EH, Gans RO, ter Maaten JC, Tangelder GJ, Donker AJ, 2002; 3: 391–97.
Stehouwer CD. Impaired skin capillary recruitment in essential 77 Watt GCM, Harrap SB, Foy CJW, et al. Abnormalities of
hypertension is caused by both functional and structural capillary glucocorticoid metabolism and the renin-angiotensin system: a four-
rarefaction. Hypertension 2001; 38: 238–42. corners approach to the identification of genetic determinants of
49 O’Rourke MF, Staessen JA, Vlachopoulos C, Duprez D, Plante GE. blood pressure. J Hypertens 1992; 10: 473–82.
Clinical applications of arterial stiffness: definitions and reference 78 Iwai N, Ohmichi N, Hanai K, Nakamura Y, Kinoshita M. Human
values. Am J Hypertens 2002; 15: 426–44. SA gene locus as a candidate gene locus for essential hypertension.
50 Luft FC. Twins in cardiovascular genetic research. Hypertension Hypertension 1994; 23: 375–80.
2001; 37 (part 2): 350–56. 79 Siffert W, Rosskopf D, Siffert G, et al. Association of a human G-
51 Geller DS, Rodriguez-Soriano J, Vallo Boado A, et al. Mutations in protein 3 subunit variant with hypertension. Nat Genet 1998; 18:
the mineralocorticoid receptor gene cause autosomal dominant 45–48.
pseudohypoaldosteronism type I. Nat Genet 1998; 19: 279–81. 80 Sharma P, Hingorani A, Jia H, et al. Positive association of tyrosine
52 Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hydroxylase microsatellite marker to essential hypertension.
hypertension. Cell 2001; 104: 545–56. Hypertension 1998; 32: 676–82.
53 Lander E, Kruglyak L. Genetic dissection of complex traits: 81 Ferrandi M, Bianchi G. Genetic mechanisms underlying the
guidelines for interpreting and reporting linkage results. Nat Genet regulation of urinary sodium excretion and arterial blood pressure:
1995; 11: 241–49. the role of adducin. Acta Physiol Scand 2000; 168: 187–93.
54 Higaki J, Baba S, Katsuya T, et al. Deletion allele of angiotensin- 82 Matsuoka Y, Li X, Bennett V. Adducin: structure, function and
converting enzyme gene increases risk of essential hypertension in regulation. Cell Mol Life Sci 2000; 57: 884–95.
Japanese men. The Suita Study. Circulation 2000; 101: 2060–65. 83 Glorioso N, Filigheddu F, Troffa C, et al. Interaction of the 1-
55 Luft FC, Miller JZ, Grim CE, et al. Salt sensitivity and resistance of Na,K-ATPase and Na,K,2Cl-cotransporter genes in human essential
blood pressure: age and race as factors in physiological responses. hypertension. Hypertension 2001; 38: 204–09.
Hypertension 1991; 17 (suppl I): I·102–08. 84 Tsujita Y, Baba S, Yamauchi R, et al. Association analyses between
56 Price DA, Fisher NDL, Lansang MC, Stevanovic R, Williams GH, genetic polymorphisms of endothelial nitric oxide synthase gene and
Hollenberg NK. Renal perfusion in blacks. Alterations caused by hypertension in Japanese: The Suita Study. J Hypertens 2001; 19:
insuppressibility of intrarenal renin with salt. Hypertension 2002; 40: 1941–48.
186–89. 85 Iwai N, Baba S, Mannami T, Ogihara T, Ogata J. Association of a
SEMINAR
sodium channel alpha subunit promoter variant with blood pressure. 24-h ambulatory blood pressure and heart rate: a study in 352
J Am Soc Nephrol 2002; 13: 80–85. normotensive Danish subjects. Am J Hypertens 1997; 10: 483–91.
86 Julier C, Delépine M, Keavney B, et al. Genetic susceptibility for 113 Collins R, MacMahon S. Blood pressure, antihypertensive drug
human familial essential hypertension in a region of homology with treatment and the risks of stroke and of coronary heart disease.
blood pressure linkage on rat chromosome 10. Hum Mol Genet 1997; Br Med Bull 1994; 50: 272–98.
6: 2077–85. 114 Staessen JA, Wang JG, Thijs L. Cardiovascular prevention and
87 Nakayama T, Soma M, Kanmatsuse K. Organization of the human blood pressure reduction: a meta-analysis. Lancet 2001; 358:
prostacyclin synthase gene and association analysis of a novel CA 1305–15.
repeat in essential hypertension. Adv Exp Med Biol 1997; 433: 115 Staessen JA, Wang JG, Thijs L. Calcium-channel blockade and
127–30. cardiovascular prognosis: recent evidence from clinical outcome
88 Frossard PM, Lestringant GG. Association between a dimorphic site trials. Am J Hypertens 2002; 15: 85S–93S.
on chromosome 12 and clinical diagnosis of hypertension in three 116 Forette F, Seux ML, Staessen JA, et al. The prevention of dementia
independent populations. Clin Genet 1995; 48: 284–87. with antihypertensive treatment. New evidence from the Systolic
89 Wilson AF, Elston RC, Tran LD, Siervogel RM. Use of robust sib- Hypertension in Europe (Syst-Eur) Study. Arch Intern Med 2002;
pair method to screen for single-locus, multiple-locus, and 162: 2046–52.
pleiotrophic effects: application to traits related to hypertension. 117 SHEP Cooperative Research Group. Prevention of stroke by
Am J Hum Genet 1991; 48: 862–72. antihypertensive drug treatment in older persons with isolated systolic
90 Wu DA, Bu X, Warden CH, et al. Quantitative trait locus mapping hypertension. Final results of the Systolic Hypertension in the Elderly
of human blood pressure to a genetic region at or near the Program (SHEP). JAMA 1991; 265: 3255–64.
lipoproteinase gene locus on chromosome 8p22. J Clin Invest 1996; 118 Prince MJ, Bird AS, Blizard RA, Mann AH. Is the cognitive function
97: 2111–18. of older patients affected by antihypertensive treatment? Results from
91 Ying LH, Zee RY, Griffiths LR, Morris BJ. Association of a RFLP 54 months of the Medical Research Council’s treatment trial of
for the insulin receptor gene, but not insulin, with essential hypertension in older adults. BMJ 1996; 312: 801–05.
hypertension. Biochem Biophys Res Comm 1991; 181: 486–92. 119 PROGRESS Collaborative Group. Randomised trial of a perindopril-
92 Hopkins PN, Hunt SC, Jeunemaitre X, et al. Angiotensinogen based blood-pressure-lowering regimen among 6105 individuals with
genotype affects renal and adrenal responses to angiotensin II in prior stroke or transient ischaemic attack. Lancet 2001; 358:
essential hypertension. Circulation 2002; 105: 1921–27. 1033–41.
93 Turner ST, Schwartz GL, Chapman AB, Dallas Hall D, 120 Zipfel GJ, Lee JM, Choi DW. Reducing calcium overload in the
Boerwinkle E. Antihypertensive pharmacogenetics: getting the right ischemic brain. N Engl J Med 1999; 341: 1543–44.
drug into the right patient. J Hypertens 2001; 19: 1–12. 121 MacMahon S, Sharpe N, Gamble G, et al. Randomized, placebo-
94 Tribut O, Lessard Y, Reymann JM, Allain H, Bentué-Ferrer D. controlled trial of the angiotensin-converting enzyme inhibitor,
Pharmacogenomics. Med Sci Monit 2002; 8: RA152–63. ramipril, in patients with coronary or other occlusive arterial disease.
95 Bianchi G, Tripodi G, Casari G, et al. Two point mutations within J Am Coll Cardiol 2000; 36: 438–43.
the adducin genes are involved in blood pressure variation. 122 Teo KK, Burton JR, Buller CE, et al. Long-term effects of
Proc Natl Acad Sci USA 1994; 91: 3999–4003. cholesterol lowering and angiotensin-converting enzyme inhibition on
96 Staessen JA, Wang JG, Brand E, et al. Effects of three candidate coronary atherosclerosis. The Simvastatin/Enalapril Coronary
genes on prevalence and incidence of hypertension in a Caucasian Atherosclerosis Trial (SCAT). Circulation 2000; 102: 1748–54.
population. J Hypertens 2001; 19: 1349–58. 123 Heart Outcomes Prevention Evaluation Study Investigators. Effects
97 Wang JG, Staessen JA, Tizzoni L, et al. Renal function in relation to of ramipril on cardiovascular and microvascular outcomes in people
three candidate genes. Am J Kidney Dis 2001; 38: 1158–68. with diabetes mellitus: results of the HOPE study and MICRO-
HOPE substudy. Lancet 2000; 355: 253–59.
98 Balkestein EJ, Wang JG, Struijker Boudier HAJ, et al. Carotid and
femoral intima-media thickness in relation to three candidate genes in 124 The Heart Outcomes Prevention Evaluation Study Investigators.
a Caucasian population. J Hypertens 2002; 20: 1551–61. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on
cardiovascular events in high-risk patients. N Engl J Med 2000; 342:
99 Ferrari P, Ferrandi M, Tripodi G, et al. PST 2238: a new
145–53.
antihypertensive compound that modulates Na,K-ATPase in genetic
hypertension. J Pharmacol Exp Ther 1999; 288: 1074–83. 125 Parving HH, Lehnert H, Bröchner-Mortensen J, et al. The effect of
irbesartan on the development of diabetic nephropathy in patients
100 Psaty BM, Smith NL, Hekbert SR, et al. Diuretic therapy, the -
with type 2 diabetes. N Engl J Med 2001; 345: 870–78.
adducin gene variant, and the risk of myocardial infarction or stroke
in persons with treated hypertension. JAMA 2002; 287: 1680–90. 126 Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on
renal and cardiovascular outcomes in patients with type 2 diabetes
101 Denton D, Weisinger R, Mundy NI, et al. The effect of increased salt
and nephropathy. N Engl J Med 2001; 345: 861–69.
intake on blood pressure of chimpanzees. Nat Med 1995; 1: 1009–16.
127 Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of
102 Graudal N, Galløe AM, Garred P. Effects of sodium restriction on the angiotensin-receptor antagonist irbesartan in patients with
blood pressure, renin, aldosterone, catecholamines, cholesterols, and nephropathy due to type 2 diabetes. N Engl J Med 2001; 345:
triglycerides: a meta-analysis. JAMA 1998; 279: 1383–91. 851–60.
103 Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure 128 Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs
of reduced dietary sodium and the dietary approaches to stop amlodipine on renal outcomes in hypertensive nephrosclerosis.
hypertension (DASH) diet. N Engl J Med 2001; 344: 3–10. JAMA 2001; 285: 2719–28.
104 Uzu T, Ishikawa K, Fujii T, Nakamura S, Inenaga T, Kimura G. 129 Fleckenstein A, Frey M, Thimm F, Fleckenstein-Grün G. Excessive
Sodium restriction shifts circadian rhythm of blood pressure from mural calcium overload—a predominant causal factor in the
nondipper to dipper in essential hypertension. Circulation 1997; 96: development of stenosing coronary plaques in humans.
1859–62. Cardiovasc Drugs Ther 1990; 4: 1005–14.
105 Weinberger MC, Fineberg NS, Fineberg SE, Weinberger M. Salt 130 Pitt B, Byington RP, Furberg CD, et al. Effect of amlodipine on the
sensitivity, pulse pressure, and death in normal and hypertensive progression of atherosclerosis and the occurrence of clinical events.
humans. Hypertension 2001; 27 (part 2): 429–32. Circulation 2000; 102: 1503–10.
106 Tuomilehto J, Jousilahti P, Rastenyte D, et al. Urinary sodium 131 Zanchetti A, Agabiti Rosei E, Dal Palù C, et al. The Verapamil in
excretion and cardiovascular mortality in Finland: a prospective Hypertension and Atherosclerosis Study (VHAS): results of long-
study. Lancet 2001; 357: 848–51. term randomized treatment with either verapamil or chlorthalidone
107 Morimoto A, Uzu T, Fujii T, et al. Sodium sensitivity and on carotid intima-media thickness. J Hypertens 1998; 16: 1667–76.
cardiovascular events in patients with essential hypertension. Lancet 132 Simon A, Gariépy J, Moyse D, Levenson J. Differential effects of
1997; 350: 1734–37. nifedipine and co-amilozide on the progression of early carotid wall
108 Omvik P, Lund-Johansen P. Is sodium restriction effective treatment changes. Circulation 2001; 103: 2949–54.
of borderline and mild essential hypertension? A long-term 133 Zanchetti A, Bond G, Hennig M, et al. Calcium antagonist lacidipine
haemodynamic study at rest and during exercise. J Hypertens 1986; 4: slows down progression of asymptomatic carotid atherosclerosis.
535–41. Principal results of the European Lacidipine Study on Atherosclerosis
109 Beilin LJ. Alcohol, hypertension and cardiovascular disease. (ELZA), a randomized, double-blind, long-term trial. Circulation
J Hypertens 1995; 13: 939–42. 2002; 106: r47–r52.
110 Staessen J, Fagard R, Lijnen P, Amery A. Body weight, sodium 134 Lichtlen PR, Hugenholtz PG, Rafflenbeul W, et al. Retardation of
intake and blood pressure. J Hypertens 1989; 7 (suppl 1): S19–23. coronary artery disease in humans by the calcium-channel blocker
111 Fagard R. Exercise characteristics and the blood pressure response to nifedipine: results of the INTACT Study (International Trial on
dynamic physical training. Med Sci Sports Exercise 2001; 33 (suppl): Antiatherosclerotic Therapy). Cardiovasc Drugs Ther 1990; 4:
S484–92. 1047–68.
112 Mikkelsen KL, Wiinberg N, Hoegholm A, et al. Smoking related to 135 Blood Pressure Lowering Treatment Trialists’ Collaboration.
SEMINAR
Effect of ACE inhibitors, calcium antagonists, and other blood morbidity and mortality in patients with sever heart failure.
pressure-lowering drugs: results of prospectively designed N Engl J Med 1999; 341: 709–17.
overviews of randomised trials. Lancet 2000; 356: 1955–64. 141 Stevenson LW. Beta-blockers for stable heart failure. N Engl J Med
136 Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular 2002; 346: 1346–47.
morbidity and mortality in the Losartan Intervention For Endpoint 142 Exner DV, Dries DL, Domanski MJ, Cohn JN. Lesser response to
reduction in hypertension study (LIFE): a randomised trial against angiotensin-converting-enzyme inhibitor therapy in black as
atenolol. Lancet 2002; 359: 995–1003. compared with white patients with left ventricular dysfunction.
137 Messerli FH, Grossman E, Goldbourt U. Are beta-blockers N Engl J Med 2001; 344: 1351–57.
efficacious as first-line therapy for hypertension in the elderly?
143 Dickstein K, Kjekshus J, and the OPTIMAAL Steering Committee,
A systematic review. JAMA 1998; 279: 1903–07.
for the OPTIMAAL Study Group. Effects of losartan and captopril
138 The ALLHAT Officers and Coordinators for the ALLHAT on mortality and morbidity in high-risk patients after acute
Collaborative Research Group. Major outcomes in high-risk
myocardial infarction: the OPTIMAAL randomised trial. Lancet
hypertensive patients randomized to angiotensin-converting
2002; 360: 752–60.
enzyme inhibitor or calcium channel blocker vs diuretic. The
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart 144 Gheorghiade M, Goldstein S. -blockers in the post-myocardial
Attack Trial (ALLHAT). JAMA 2003; 288: 2981–97. infarction patient. Circulation 2002; 106: 394–98.
139 The ALLHAT Officers and Coordinators for the ALLHAT 145 Sareli P, Radevski IV, Valtchanova ZP, et al. Efficacy of different
Collaborative Research Group. Major cardiovascular events drug classes used to initiate antihypertensive treatment in black
in hypertensive patients randomized to doxazosin vs chlorthalidone. subjects. Results of a randomized trial in Johannesburg, South
The Antihypertensive and Lipid-Lowering Treatment to Africa. Arch Intern Med 2001; 161: 965–71.
Prevent Heart Attack Trial (ALLHAT). JAMA 2000; 283: 146 Dickerson JEC, Hingorani AD, Ashby MJ, Palmer CR, Brown MJ.
1967–75. Optimisation of antihypertensive treatment by crossover rotation of
140 Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on four major classes. Lancet 1999; 353: 2008-2013.
Clinical picture
Homozygous familial hypercholesterolaemia in identical twins
J Zschocke, J R Schaefer
At the age of 2 years, two identical twin

boys of Turkish origin (figure) were
referred for investigation of symmetrical
skin lesions on ellbows, knees, hands,
and ankles. Lipid analyses revealed
massive hypercholesterolaemia, with total
cholesterol of 1250/1140 mg/dL, LDL
cholesterol of 1180/1080 mg/dL, and
Lp(a) of 130/130 mg/dL, respectively, in
the two children. The parents, who were
consanguineous, both suffered from
previously undiagnosed familial hyperc-
holesterolaemia. Family history was
surprisingly unremarkable with regard to
cardiovascular disease. Conservative
treatment with diet and various lipid-
lowering drugs in the children failed to
sufficiently reduce plasma cholesterol
levels. At the age of three years, the
xanthomas were markedly increased,
and LDL apheresis therapy was
initiated. To our knowledge these are
the youngest children with LDL-
receptor deficiency reported in the
literature. The occurrence of identical
skin lesions in the children was an
important factor for early diagnosis— Department of Paediatrics and Institute of Human Genetics, Ruprecht-Karls-University,
being an identical twin may sometimes 69120 Heidelberg, Germany (J Zschockel MD); Department of Internal Medicine,
have unexpected advantages. Cardiology, Philipps-University, 35033 Marburg, Germany (J R Schaefer MD)

Essential Hypertension

Uploaded by

Copyright:

Available Formats

Essential Hypertension

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Essential Hypertension

Uploaded by

Copyright:

Available Formats

SEMINAR

Jan A Staessen, Jiguang Wang, Giuseppe Bianchi, Willem H Birkenhäger

Essential hypertension refers to a lasting increase in blood Epidemiology

THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com 1629

1630 THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com

predictive superiority of ambulatory over conventional

THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com 1631

White-coat hypertension Masked hypertension exchange and, through calcium-

1632 THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com

Panel 2: Mendelian forms of blood pressure dysregulation

Syndrome* Phenotype† Mutation‡ Mechanism

THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com 1633

Phenotype Effect A second layer of complexity in the study of blood

1634 THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com

hypertension.96 In caucasian people, the mutated 70 Hypertension 900 Femoral intima-media

Incidence per 100 patients

daily sodium excretion by 100 mmol (about 6 g of salt),

THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com 1635

Glucocorticoid receptor77 , , subunits of epithelial 11-hydroxylase, aldosterone QTL on human 12q21.3374

1636 THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com

Group Relative risk (95%) versus chlorthalidone

THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com 1637

1638 THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com

THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com 1639

1640 THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com

At the age of 2 years, two identical twin

THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com 1641

You might also like