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
causes. Its prevalence rises with age, irrespective of the
type of blood pressure measurement and the operational
thresholds used for diagnosis (panel 1). In developed and
developing countries alike, essential hypertension affects
25–35% of the adult population, and up to 60–70% of
those beyond the seventh decade of life. Hypertension
aggregates with other cardiovascular risk factors, such as
abdominal obesity, dyslipidaemia, glucose intolerance,
hyperinsulinaemia, and hyperuricaemia, possibly because
of a common underlying cause.
We will review developments in the epidemiology,
diagnosis, pathophysiology, genetics, and treatment of
essential hypertension. During the past decade, these
disciplines have progressed towards substantial new
insights. Nevertheless, despite relentless research efforts,
the specific causes of essential hypertension remain
incompletely understood. We will therefore emphasise the
need for improved integration of multidisciplinary
research to clarify the pathophysiology of this complex
and multifaceted disorder.
Lancet 2003; 361: 1629–41
Studiecoördinatiecentrum, Hypertensie en Cardiovasculaire
Revalidatie Eenheid, Departement voor Moleculair en
Cardiovasculair Onderzoek, Katholieke Universiteit Leuven, Leuven,
Belgium (J A Staessen MD, J Wang MD); Divisione di Nefrologia
Dialisi e Ipertensione, Ospedale San Raffaele, Dipartimento di
Scienze e Techologie Biomediche, Universitá Vita-Salute, Milano,
Italy (Prof G Bianchi MD); and Erasmus University, Rotterdam,
Netherlands (Prof W H Birkenhäger MD)
Correspondence to: Dr Jan A Staessen, Study Coordinating Centre,
Laboratory of Hypertension, University of Leuven, Campus
Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium
(e-mail: jan.staessen@med.kuleuven.ac.be)
In cross-sectional and longitudinal population studies,
systolic blood pressure increases with age until the eighth
decade of life (figure 1). By contrast, diastolic blood
pressure rises only until 50 years of age, after which it
either becomes constant or even decreases slightly. In the
Framingham Heart Study,1 increasing age entailed a shift
from diastolic pressure to systolic pressure and then to
pulse pressure as the main predictor of cardiovascular
risk. Below age 50 years, diastolic pressure was the
strongest predictor. Age 50–59 years was a transition
period when all three blood pressure indices were similar
predictors, and from 60 years on, diastolic pressure was
negatively related to the risk of coronary events, so that
pulse pressure became a superior predictor to systolic
pressure.1 The finding that in middle-aged and older
patients cardiovascular outlook gets worse with raised
pulse pressure—rather than mean pressure—is consistent
in men and women, in treated and untreated
hypertensive individuals,2 and in patients with a history of
myocardial infarction3 or renal failure.4 Furthermore, in
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
Search strategy
We identified original research papers, reviews, and editorial
comments by going through leading journals that publish
basic and clinical research in the field of hypertension, and
by electronically searching the Medline database. We
directed special attention to papers published since 1997.
We reviewed consensus documents on automated blood
pressure measurement as well as guidelines for the
management of hypertension. We also looked for research
developments by discussions with our collaborators and with
specialists in the clinical or fundamental aspects of
cardiovascular medicine

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 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

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GLOSSARY
EPIGENETIC MECHANISM
A term used to describe non-mutational occurences, such as DNA
methylation and histone modification, which change the expression of a
gene. Histones are proteins around which double-stranded DNA is coiled
and make up the core of a nucleosome, the most fundamental unit of
DNA packaging in the nucleus.
IMPRINTS
Genetic imprinting is any mechanism by which individual cells express
the maternal or paternal allele of a gene, but not both. Although
commonly used in relation to autosomal genes, X chromosome
inactivation is a form of imprinting.
PENETRANCE
The extent to which a person carrying a defined allele has an altered
phenotype.
RECOMBINATION MAXIMA
Recombination is the crossover of chromosome fragments between the
maternal and paternal homologues of each chromosome pair during the
meiosis, the specialised cell division giving rise to sperm and egg cells.
Recombination maximum refers to the location along the chromosome
at which recombination is most likely to occur.
SYNTENY
The property of genes to be localised on the same chromosome across
species. Conservation of synteny shows that a group of genes which is
on one chromosome in one species are similarly linked in a second
species.
high-to-normal blood pressure, as defined in panel 1, is
associated with an increased risk of cardiovascular disease6
and incidence of hypertension.11 Compared with optimum
blood pressure, high-normal blood pressure was
associated with a risk-factor-adjusted hazard ratio for
cardiovascular disease of 2·5 in women and 1·6 in men.6
Similarly, the incidence of hypertension rose stepwise
across the non-hypertensive blood pressure categories.
Below age 65, the 4-year rates were 5·3% in patients with
optimum blood pressure, 17·6% in those with normal
blood pressure, and 37·3% in those with high-normal
blood pressure.11 Corresponding 4-year rates of
progression to hypertension in subjects of 65 years and
older were 16·0%, 25·5%, and 49·5%, respectively.11
Diagnosis
For the diagnosis of hypertension, doctors rely mainly on
Riva-Rocci’s technique and the auscultation of the
Korotkoff sounds. Raised clinic blood pressure readings
have to be confirmed on at least two visits with intervals
dependent on the height of the blood pressure, presence
of target organ damage, and other cardiovascular risk
factors.10,12,13 Nowadays, automated blood pressure
measurement is increasingly used in clinical practice,
mainly for diagnosis of the white-coat syndrome, which
consists of a transient rise of a patient’s blood pressure in
response to the medical environment or the observer
recording the blood pressure. The accuracy of devices for
measurement of blood pressure should be assessed in
validation studies according to internationally recognised
protocols14 and published in peer-reviewed journals.
Diagnostic thresholds are available for different types of
automated blood pressure measurement in adults
(panel 1), whereas those for children and adolescents are
still under discussion.15
Ambulatory monitoring substantially refines the risk
stratification provided by conventional sphygmomanom-
etry, both in hypertensive patients16 and in the general
population.17 The greater number of measurements, the
absence of digit preference and observer bias, and the
reduction of the white-coat effect contribute to the
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SEMINAR
predictive superiority of ambulatory over conventional
blood pressure. Additionally, a blunted fall in nocturnal
blood pressure is a harbinger of an unfavourable outcome,
irrespective of whether the decrease is assessed as a
continuous18 or a dichotomous characteristic.19 In clinical
practice, the commonly used definition of white-coat
hypertension is raised clinic blood pressure in the
presence of a normal daytime ambulatory blood
pressure.20,21 Results of event-based studies16,22 have clearly
shown that the risk of cardiovascular disease is lower in
patients with white-coat hypertension than in those with
raised ambulatory blood pressure, even after controlling
for concomitant risk factors. When daytime ambulatory
blood pressure was below 130 mm Hg systolic and
80 mm Hg diastolic, the incidence of cardiovascular
disorders did not differ between normotensive people and
those with white-coat hypertension.16,20 The counterpart of
white-coat hypertension is masked hypertension, a disorder
characterised by a normal conventional blood pressure
confirmed on repeated clinic visits, but a raised daytime
ambulatory blood pressure.23,24 Preliminary observations
suggest that this condition is associated with more target
organ damage than that noted in patients with sustained
normotension.23,24
Self-measurement of blood pressure at home is cheaper
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
wrist devices is not recommended.14 To ensure a reliable
report of home blood pressure readings as instructed by a
professional, values must be downloaded from the memory
of a device or printed. If applied correctly, self-
measurement accomplishes several of the advantages of
ambulatory monitoring, including the increased number of
readings, the absence of the white-coat syndrome, and
(when automated devices are used) the absence of observer
bias. Furthermore, self-measurement could increase
compliance to prescribed drugs and reduce the number of
clinic visits required for the diagnosis and the treatment of
hypertension.25 Diagnostic thresholds have been proposed
(panel 1),26 but they have not yet been widely validated by
prospective outcome studies.27
Conventional measurement remains the standard
method for assessment of blood pressure. In patients with
raised clinic blood pressure and either target organ damage
or a high cardiovascular risk profile, treatment can be
started without confirmation of the increased clinic
readings by automated measurement techniques. However,
when raised blood pressure is the only detectable
abnormality or when patients with a normal clinic blood
pressure show unexplained target-organ damage, self-
measurement, ambulatory monitoring, or both must be
used to exclude white-coat hypertension or masked
hypertension, respectively (figure 2). In the absence of
other cardiovascular risk factors and signs of target organ
damage, treatment of patients with white-coat
hypertension can be restricted to lifestyle measures and
yearly follow-up of ambulatory blood pressure.28
Pathophysiology
Sodium and fluid balance and vasomotor tone are
cornerstones in blood pressure regulation. Both
mechanisms are affected by numerous genetic and
environmental factors, and are controlled by hormonal,
nervous system, paracrine, and intracellular feedback
loops. The interactions between these factors change with
age, and account for the heterogeneous pattern of the
haemodynamic alterations that lead to and sustain high
blood pressure throughout life.
1631
 SEMINAR
White-coat hypertension
(Isolated clinic hypertension)
Persistently raised
clinic blood pressure
Yes
Target organ damage?
No
High
Home Start
Low
treatment
24-h ambulatory High
blood pressure
Low
Continue to monitor
clinic and home
blood pressure
Figure 2: Guidelines for assessment of patients by use of clinic, home, and ambulatory
monitoring of blood pressure
Modified from reference 21. For definitions of normotension and hypertension, see panel 1.
Sodium and fluid balance
According to pioneering research29 and subsequent
evidence,30 the kidneys play a central part in the
pathophysiology of essential hypertension. Blood pressure
starts to rise when the kidney requires a higher than usual
blood pressure to maintain extracellular fluid volume
within normal limits.29 Models of essential hypertension in
rats share the characteristic that renal sodium excretion is
impaired at any degree of blood pressure.31 In rats32 and
man,33 transplantation of a kidney from a normotensive
donor reduces the blood pressure. Such findings32,33 do not
suggest that the disturbance causing essential
hypertension only affects the kidneys. Indeed, essential
hypertension is characterised by generalised membrane
abnormalities,34 which could affect the function of many
organs in various ways.
The central role of the kidney in the pathogenesis of
hypertension should be differentiated from salt sensitivity.
Secondary forms of hypertension,
pheochromocytoma or hyperaldosteronism, can also be
associated with a reduced ability of the kidneys to excrete
a sodium load. In such cases, removal of the primary
cause of hypertension corrects the enhanced renal sodium
reabsorption. In genetic forms of hypertension, salt-
sensitivity may result from various mutations affecting
cytoskeleton proteins,35,36 ion transporters,34 or endocrine
factors37,38 that control renal sodium handling. In other
forms of hypertension, salt-sensitivity originates in an
imbalance between the hormonal,39 nervous,40 or
haemodynamic29 regulations that affect sodium balance
through changes in glomerular filtration or tubular
reabsorption.
The hormone ouabain is released endogenously from
the adrenal glands and possibly from the midbrain41 in
response to hypoxia41 or expansion of the extracellular
fluid volume induced by aldosterone.42 Evidence suggests
that, dependent on its concentration, this hormone
behaves as a versatile modulator of the ubiquitously
expressed sodium pump.39 In renal tubular cells,
inhibition of Na
/K
ATPase activity by ouabain
promotes natriuresis. In cardiac and vascular myocytes,
this process could slow the sarcolemmal Na
/Ca2

1632
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Masked hypertension exchange and, through calcium-
(Isolated ambulatory
dependent pathways, stimulate
hypertension) excitation-contraction coupling and
the expression of growth-related
genes.34,38 At very low concentrations
Persistently normal within the nanomolar range,
clinic blood pressure endogenous ouabain may increase
the size of the membrane pool of
active sodium pumps43 and by this or
Target organ damage? other unknown mechanisms lead to
renal sodium conservation rather than
Yes loss of salt.39
High
24-h ambulatory Stimulation of the renal sympathetic
blood pressure nerves and activation of the renin-
angiotensin system promote sodium
and fluid retention. Interactions
between both pathways of sodium
handling occur intrarenally as well as
extrarenally. Circulating angiotensin II
Continue to monitor facilitates the presynaptic release of
clinic and ambulatory noradrenaline.40 It can also directly
blood pressure increase sympathetic outflow from the
subfornical organ and the area
postrema, two specialised areas within
the central nervous system that lack a
blood-brain barrier.44 Furthermore,
angiotensin II itself acts as a
peptidergic neurotransmitter in the brain.45 Angiotensin II,
originating from neurons in the paraventricular nucleus,
attenuates the reflex modulation of sympathetic outflow
from the brain and activates sympathetic preganglionic
neurons. These central effects of angiotensin II are greatest
during a low sodium diet (high renin activity), least during
high sodium intake (low renin activity), and tonic during
normal sodium diet.40
Microvascular and macrovascular mechanisms
Increased peripheral arterial resistance is the hallmark of
essential hypertension. The active component of arteriolar
resistance depends on the contraction of vascular smooth
muscle cells. Structural changes in the wall-to-lumen ratio
are termed vascular remodelling.46 Histopathological
studies of gluteal arterioles mounted on wire myographs
have shown that resistance vessels of hypertensive patients
have a reduced lumen, an increased media-to-lumen ratio,
such as but a normal medial cross-sectional area.46 Experimental
evidence favours the notion that these morphological
alterations arise as an adaptation to the increased blood
pressure through changes in the neurohumoral milieu,
and that they amplify rather than cause increase of blood
pressure.47 Vascular hypertrophy associated with
hypertension can also lead to closure of small vessels.48
Vascular rarefaction could therefore contribute to the
increased vascular resistance in long-standing
hypertension.
Isolated systolic hypertension in older patients is a
separate disease entity due to stiffening of the large
arteries with advancing age. Aortic pulse wave velocity, an
index of arterial stiffness, doubles between 15 and
70 years of age.49 The arterial pressure wave consists of a
forward component generated by the heart and reflected
waves returning to the heart from peripheral sites.4,49 In
healthy young adults, the reflected waves coincide with
diastole, raise diastolic pressure, and boost coronary
perfusion. With arterial stiffening, which arises with
ageing or in advanced hypertension, the reflected waves
move faster, reach the proximal aorta during systole, and
cause an augmentation of late systolic pressure, whereas
diastolic pressure decreases.4,49 Lowered diastolic pressure
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 SEMINAR

can impair coronary blood flow and predispose to
myocardial ischaemia. Increased systolic pressure
augments cardiac work and can lead to heart failure. The
age-related changes in the elastic properties of the large
arteries and in the wave reflections also account for the
greater brachial artery pressure than central aortic
pressure in young patients, whereas in the elderly or in
patients with end-stage renal disease4 both values tend to
be similar.
Genetics of human hypertension
More than 40 years ago, at the time of the controversy
between Sir George Pickering and Robert Platt,
researchers had already noticed that hypertension runs in
families. Population-based studies show correlation
coefficients between relatives, usually in the range
0·1–0·3. Parent-offspring correlations tend to be smaller
than those among siblings. Heritability estimates,
generally based on complex biometrical assumptions and
Mendelian mechanisms of inheritance, cluster around
20% in family studies, but in twin studies they vary
around 60%.50
Monogenic forms of blood pressure dysregulation
The last decade witnessed tremendous progress in high-
throughput genomics and proteomics, which allow many
samples to be processed in a short time, as well as in cell
and molecular biology. Technological advances led to the
discovery of 17 human genes (panel 2)52 that cause
Mendelian forms of either hypertension or hypotension.

Panel 2: Mendelian forms of blood pressure dysregulation

Syndrome* Phenotype† Mutation‡ Mechanism

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

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 SEMINAR
Phenotype Effect
Nucleus Multiple genes
Proteins and
subcellular IP
organelles
Host factors
Cell IP (race, sex, age, etc)
Tissue IP
Whole BP Environment
organism HT Lifestyle
Figure 3: Schematic representation of blood pressure as a
complex multigenic trait, affected by host and environmental
factors and feedback control
IP=intermediate phenotypes. BP=blood pressure. HT=hypertension.
Curved arrows represent feedback loops.
However, monogenic disorders of blood pressure
regulation are rare and do not explain blood pressure
variability in the population at large.53
Blood pressure as a polygenic quantitative trait
Until now, geneticists have failed to identify common
genes with large effects on human hypertension. It is
conceivable that such genes do not exist and that blood
pressure is dependent on a mosaic of many loci, each
with a small influence or with a contribution differing
according to sex,54 race,55,56 age,51,55 or lifestyle. However,
many studies57 have limitations such that the existence of
major genes controlling blood pressure cannot yet be
completely ruled out. Lack of standardisation and
arbitrary dichotomisation of a continuous and variable
phenotype, inappropriate selection of cases and controls,
population admixture and stratification, insufficient
sample size, and failure to account for confounders,
environmental factors, or EPIGENETIC MECHANISMS,
remain key obstacles to substantial progress.
Other reasons could also account for the shortfall, but
they are generally underappreciated. First, in most
people, blood pressure behaves as an age-related
quantitative trait (figure 1). Advancing age increases salt
sensitivity,58 steepens the relationship between blood
pressure and exchangeable body sodium,59 decreases the
gain of the baroreceptor reflex,60 reduces renal
perfusion,61 and compromises the buffering effects of the
large arteries on both systolic and diastolic blood
pressure.62 Throughout life, genetically determined host
factors continuously interact with environmental
influences, including lifestyle (figure 3). Any resulting
change in blood pressure is initially counteracted by self-
organising homoeostatic mechanisms, which encompass
intracellular signalling, metabolic and hormonal
regulation at cell and tissue levels, as well as systemic
feedback loops involving the whole body. For instance,
acutely induced hypertension causes a rapid shift in
sodium pump activity from proximal to distal sites of the
nephron.63 Since findings obtained under controlled
experimental conditions or in defined populations cannot
be easily generalised, this innate plasticity of living
organisms (figure 3) should be incorporated into the
search for genes that may cause essential hypertension in
man.
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A second layer of complexity in the study of blood
pressure as a quantitative trait originates from the
inconsistency of the relationship between phenotype and
genotype. Many genes might influence the same
phenotype, or a sole mutation could be associated with
grossly discordant phenotypes.64 Even in monogenic
disorders with typical Mendelian inheritance (panel 2),
PENETRANCE may vary according to race,55 age,51,55 dietary
salt intake,51 hormonal milieu,37,38 or just from one case to
another.64 Mendelian principles or the biometrical
assumptions underlying the decomposition of variance
into genetic, environmental, and random components,
might not apply to multigenic quantitative traits. Indeed,
cardiovascular phenotypes are affected by distinct
maternal and paternal genomic IMPRINTS that result in a
divergent expression of parental alleles during fetal
development and postnatal growth into adulthood.65
Offspring inherit their mitochondrial DNA mainly66 but
not exclusively67 from their mother. Maternal and paternal
chromosomes show differences in location of
RECOMBINATION MAXIMA.68 The intrauterine environment
might affect the occurrence of cardiovascular disease later
in life and is largely controlled by genetic and
environmental factors linked to the mother.69 Finally,
epigenetic mechanisms may lead to transdifferentiation,
whereby specialised cells can undergo profound changes
in their function.70
How, then, can researchers cope with the complexity of
human essential hypertension? Some experts favour the
whole genome approach71–74 and exploit SYNTENY between
species75 in the search for major genes that could lead to
hypertension. Inbred rats and genetically-engineered
mice, in which gene activities have been specifically
manipulated, produced new insights in the long-term
regulation of blood pressure.31,72 However, these rodent
models31,72 do not stand comparison with the complexity
and heterogeneous nature of the human disease. Other
investigators verified prespecified hypotheses about
known candidate genes,76 such as those listed in
panel 33,57,71,72,74,77-91 and tried to reconstruct the
pathogenesis of hypertension from cells up to the systemic
level. Under controlled laboratory conditions, they
measured intermediate phenotypes less distant from the
DNA than blood pressure, such as modulation status.92
Non-modulators show blunted renovascular and adrenal
responses to infused angiotensin II in sodium repleted and
sodium depleted conditions, respectively.92 Selective
blockade of molecular mechanisms in pharmacogenomic
experiments may constitute the final leg of the long
journey from bench to bedside.93 For instance, in patients
with a genetic predisposition to salt retention, diuretics
may lower blood pressure more than other treatments.93
However, when used in isolation, the pharmacogenomic
approach also has weakness, because a drug rarely
possesses the necessary selectivity. Moreover,
interindividual differences in pharmacokinetics could alter
drug effects irrespective of specific interference with
mechanisms that regulate blood pressure.94
The discovery of the role of adducin in human
hypertension illustrates the potential of multidisciplinary
research along the lines of a predefined pathophysiological
hypothesis. Adducin is a cytoskeleton protein.81,82
Investigations in rats,81,95 in-vitro transfection studies,35
interventions in never-treated hypertensive patients,36 and
epidemiological studies96,97 have shown a logical sequence
of events leading from a point mutation in the  subunit95
to a cellular dysfunction characterised by higher activity of
the sodium pump,35 hence increased tubular sodium
reabsorption in the kidney,36 and ultimately
THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com
 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

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For personal use. Only reproduce with permission from The Lancet Publishing Group.
 SEMINAR
Panel 3: Putative candidate genes or quantitative trait loci implicated in blood pressure regulation
Receptors Cellular or paracrine agents
Angiotensin receptors 1b and , ,  subunits of adducin81,82
257,72
Atrial natriuretic peptide 1, 2, 1 isomers of Na
K

receptor/guanylyl cyclase A72 ATPase, Na,K,2Cl-cotransporter83
Glucocorticoid receptor77 , ,  subunits of epithelial
sodium channel85
Dopamine receptors 1, 2 and Renal epithelial potassium
372,74 channel72
1b, 2, and 2 adrenergic 3 subunit of G-protein79
receptor72
Insulin receptor91 Calmodulin-dependent protein
kinase II72
Leptin receptor71 Adipsin71
Interleukin 672
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
Furthermore, antihypertensive treatment substantially
reduced the risk of heart failure, although estimates of
benefit varied across trials because of differences in the
clinical criteria used for diagnosis.
In the Systolic Hypertension in Europe (Syst-Eur)
trial,116 dementia was a pre-specified secondary endpoint.
After a median follow-up of 3·9 years, treatment starting
with the dihydropyridine calcium-channel blocker
nitrendipine reduced the rate of degenerative dementia by
55% (p<0·001).116 In view of the null results observed in
other placebo-controlled studies testing thiazides,117,118
 blockers,117,118 or monotherapy with the ACE inhibitor
perindopril,119 the Syst-Eur findings might be due to
chance rather than to blood pressure lowering or the
inhibition of calcium influx into ischaemic brain
neurons.120 Thus, the concept that antihypertensive
treatment with long-acting dihydropyridines might
protect against dementia needs further testing in
controlled clinical trials.
Secondary prevention
Several trials119,121-125 have tested the hypothesis that
inhibitors of the renin-angiotensin system might be more
effective than placebo in the secondary prevention of
stroke and the cardiovascular-renal complications of
hypertension. These drugs diminished the frequency of
cardiovascular events123,124 and stroke recurrence.119 In
diabetic patients with normoalbuminuria123 or
microalbuminuria,125 they also decreased the incidence of
overt nephropathy, but they did not reduce the rate of
progression of coronary122 or carotid121 atherosclerosis.
Furthermore, in patients with overt nephropathy due to
diabetes126,127 or hypertension,128 ACE inhibitors128 or
angiotensin receptor blockers126,127 were more effective
than conventional therapy126 or amlodipine127 in
postponing a doubling of the serum creatinine
concentration or preventing end-stage renal disease.
However, in line with Fleckenstein’s investigations in
animals,129 results of several trials have shown that long-
acting calcium-channel blockers compared with
placebo,130 diuretics131,132 or atenolol133 slowed the
progression of carotid atherosclerosis. In the International
1636
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Hormones or vasoactive Other proteins or QTLs
substances
Renin, angiotensinogen, angiotensin- SA locus78
converting enzyme57
Atrial and brain natriuretic peptides QTLs associated with X- and
Y-chromosomes72
11-hydroxylase, aldosterone QTL on human 12q21.3374
synthase
Endothelin 2 and 372 QTLs associated with Lewis
blood group and complement
C3F89
Endothelial nitric oxide synthase84 QTL associated with human
pancreatic phospholipase A288
Prostacyclin synthase87 Neuropeptide Y72
Growth hormone86 Tyrosine hydroxylase80
Corticotropin releasing hormone71 Lipoprotein lipase90
Nifedipine Trial on Antiatherosclerotic Therapy, short-
acting nifedipine (n=173) compared with placebo
(n=175) reduced the number of new coronary lesions by
28%, but the drug was associated with higher all-cause
(14 vs 2) and cardiac mortality (10 vs 2), whereas the
incidence of non-fatal cardiac events was similar in both
groups (52 vs 44).134
Comparative trials
In nine trials, 62 605 hypertensive patients were ran-
domised to initial treatment with old drugs (diuretics and
 blockers), or new agents (calcium-channel blockers and
converting-enzyme inhibitors). Compared with old drugs,
new agents offered similar overall cardiovascular
protection, but calcium-channel blockers provided more
reduction in the risk of stroke (13·5%, 95% CI
1·3–24·2%, p=0·03) and less reduction in the risk of
myocardial infarction (19·2%, 3·5–37·3%, p=0·01).114
These cause-specific outcome results confirm findings of
other investigators,135 but have wide confidence intervals,
and therefore must be interpreted with caution.
The researchers of the Losartan Intervention for
Endpoint Reduction in Hypertension Study (LIFE)136
reported that first-line treatment with losartan, compared
with atenolol, improved outcome over and beyond blood
pressure control. They measured achieved blood pressure
at the end of follow-up (mean 4·8 years) or just before an
event. This definition did not account for the differences
in systolic pressure (higher on atenolol), diastolic pressure
(lower on atenolol), or pulse pressure (higher on
atenolol), which arose during the first year of follow-up.
In addition, in older patients such as those enrolled in the
LIFE study (age range 55–80 years, mean age 66·9 years),
 blockers improve outcome less than diuretics.137
The Antihypertensive and Lipid-Lowering Treatment
to Prevent Heart Attack Trial (ALLHAT)138,139 had 42 424
participants aged 55 years or older with hypertension and
at least one other cardiovascular risk factor. They were
randomised to first-line antihypertensive therapy
with chlorthalidone (12·5 to –25·0 mg/day, n=15 255),
amlodipine (2·5–10·0 mg/day, n=9067), lisinopril
(10–40 mg/day, n=9048), or doxazosin (2–8 mg/day,
n=9054) with an intended follow-up of 4–8 years. The
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 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
non-fatal myocardial infarction, occurred in 3321
patients.138,139 Because of the twofold higher risk of heart
failure on doxazosin compared with chlorthalidone, the
doxazosin arm was stopped prematurely after a median
follow-up of 3·3 years.139 Follow-up of the other groups
lasted an average of 4·9 years.138 The key finding was that
there were no differences between randomised patients in
the primary outcome and total mortality. Compared with
chlorthalidone, treatment starting with amlodipine was
associated with a higher risk of heart failure (table).
Furthermore, heart failure, stroke, and combined
cardiovascular disease arose more frequently in patients
allocated doxazosin or lisinopril than in those of the
chlorthalidone group (table).
Interpretation of the ALLHAT results is difficult,
because at randomisation 90% of the patients were
already on antihypertensive treatment, most often
diuretics. Thus, this trial tested continuation of a diuretic
versus switching drug classes. Patients on diuretics with
latent or compensated heart failure were deprived of their
treatment when they were not randomised to
chlorthalidone. Moreover, the achieved systolic pressure
was higher with doxazosin (2·0 mm Hg),139 amlodipine
(1·1 mm Hg),138 and lisinopril (2·3 mm Hg) than with
chlorthalidone.138,139 Presumably, these factors explain why
the Kaplan-Meier curves started to diverge immediately
after randomisation for heart failure and approximately
6 months later also for stroke.115 Furthermore, the
sympatholytic agents used for step-up treatment (atenolol,
clonidine, or reserpine, at the physician’s discretion) led
to a somewhat artificial treatment regimen, which does
not accord with modern clinical practice.138
Notwithstanding these limitations, ALLHAT stands out
as the largest double-blind trial ever undertaken in
hypertensive patients. The study was managed and
analysed independent of the pharmaceutical industry.
Guidelines for antihypertensive drug therapy
In view of the evidence from clinical trials, guidelines for
the treatment of hypertension10,12,13 are under revision.
However, most experts recommend an integrated
approach of risk management to prevent the
complications of raised blood pressure. Accordingly, the
need to start treatment increases in the presence of other
cardiovascular risk factors or when absolute risk reaches a
specified threshold (for example in the British population,
a 10-year risk of coronary heart disease of 15% or
greater12).
On the basis of evidence from trials, most10,12,13 but not
all guidelines10 suggest that low-dose thiazides might be
the most cost-effective way to start pharmacological
treatment in most patients. However, for each class of
antihypertensive drugs, compelling indications or
contraindications exist.10,12,13 For instance,  blockers or
calcium-channel blockers can be used in patients with
angina pectoris. Stable heart failure is an indication for
thiazides, aldosterone receptor blockers,140  blockers,141 or
ACE inhibitors,124,142 but not for angiotensin receptor
blockers.143 A history of myocardial infarction favours the
use of  blockers144 or ACE inhibitors.124,142 Renal
impairment, microalbuminuria, or proteinuria is an
indication for ACE inhibitors123,128 or angiotensin receptor
blockers.125-128 Systolic hypertension warrants the use of
thiazides117 or long-acting dihydropyridines.115 In black
people, hypertension responds better to thiazides or
calcium-channel blockers than to inhibitors of the renin
system, in terms of both blood pressure reduction138,145 and
prevention of complications.138,142 In the absence of renal
impairment at the initiation of antihypertensive
treatment, all major drug classes equally prevent end-
stage renal disease.138
The discussion about which drug class is better suited
to start antihypertensive therapy is largely obsolete. In
most patients, several drug classes and combinations need
to be rotated to optimise treatment at acceptable
tolerance. The blood-pressure lowering activities of ACE
inhibitors and  blockers are additive to those of thiazides
and calcium-channel blockers, and vice-versa.146 Patients
younger than 50 years may be started on ACE inhibitors
or  blockers and switched to thiazides or calcium-
channel blockers if blood pressure remains uncontrolled,
whereas the reverse order can be used in those older than
50 years.146
The target of antihypertensive treatment is to achieve
normal levels of systolic and diastolic blood pressure as

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For personal use. Only reproduce with permission from The Lancet Publishing Group.
 SEMINAR
defined in panel 1. In young people and patients with
diabetes mellitus, previous cardiovascular disorders,
multiple risk factors, or renal insufficiency, blood pressure
must be lowered to within the optimum or normal range,
if possible. To achieve blood pressure control, more than
two-thirds of patients need a combination of two or more
drugs.138 A meta-regression analysis115 included 149 407
patients randomised in 30 trials. In contrast to recent
suggestions of benefit beyond blood pressure
lowering,124-127,136 this overview115 suggested that most of the
benefit of antihypertensive treatment could be explained
by the decrease in blood pressure rather than by ancillary
drug properties, and therefore shows the need for tight
blood pressure control.
Conclusions
The causes of essential hypertension are still uncertain.
For now, with few exceptions, our therapeutic approach
to essential hypertension and its cardiovascular
complications remains generic rather than specifically
targeted. The notion that the discovery of major genes or
interference with a sole pathophysiological mechanism
will substantially advance prevention and treatment is an
oversimplification that ignores the heterogeneous nature
of this disorder. Integration of genetic, molecular, clinical,
and epidemiological research could disclose the way in
which genetic and environmental factors lead to different
expression of proteins controlling the processes that cause
hypertension. This integrated approach may identify
subsets of patients in whom specific combinations of
genetic and environmental factors raise blood pressure,
and could lead to individualised treatment. Blind
treatment by trial and error could then change into
comprehensive and specific intervention with the
pathophysiological processes at work in every patient.
Contributors
All authors conceived and wrote the seminar.
Conflict of interest statement
JAS and WHB did ad-hoc consultancies for pharmaceutical companies
with commercial interests in the cardiovascular field. During their
lifetimes, they have received funding for studies, seminars, and travel from
such companies. GB is an adviser to the Prassis Sigma Tau Research
Institute (Milan, Italy).
Acknowledgments
JAS thanks Hilde Celis, Elly Den Hond, Tatiana Kuznetsova,
Tim Nawrot, Agnieszka Olszanecka, Katarzyna Stolarz, Lutgarde Thijs,
and Valérie Tikhonoff. Research cited in this review was partly sponsored
by the European Union (contracts IC15-CT98-0329-EPOGH and
QLG1-CT-2000-01137-EURNETGEN). JGW was funded by the
Bilaterale Scientific and Technological Collaboration between the
People’s Republic of China and Flanders (project BIL02/10). The
funding sources had no role in the writing of the article.
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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)

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