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ypertension is a common condition, which is increasingly prevalent with age.1 Indeed, 50% of those aged
60 years are hypertensive,2 of which the majority (80%),
have isolated systolic hypertension (ISH). This is characterized by an increase in systolic blood pressure (SBP) but a
normal or reduced diastolic blood pressure (DBP). Although
initially considered a benign consequence of ageing, ISH and
a wide pulse pressure (PP), per se, are actually pathological
and associated with a considerable increased risk of cardiovascular (CV) disease.1
In contrast to hypertension in younger subjects, ISH in older
adults results from stiffening of the central (conduit) arteries,3,4
which normally serve to buffer the cyclic changes in pressure
arising from intermittent left ventricular ejection. Traditionally,
the structural components of the arterial wall were thought to be
the major determinants of vessel stiffness. However, we5 8 and
others9 have demonstrated recently that there is a functional
regulation of conduit artery stiffness by smooth muscle tone,
which is influenced by circulating and endothelium-derived
vasoactive mediators, including NO and endothelin-1.
Received February 21, 2007; first decision March 13, 2007; revision accepted April 11, 2007.
From Clinical Pharmacology (S.M.L.W., Y., C.M.M., K.M.M-P., A.D.B., I.B.W.), University of Cambridge, Addenbrookes Hospital, Cambridge; and
the Wales Heart Research Institute (J.R.C.), University Hospital, Cardiff, United Kingdom.
Correspondence to Ian B. Wilkinson, Clinical Pharmacology, University of Cambridge, Box 110, Level 3, Addenbrookes Hospital, Hills Road,
Cambridge CB2 2QQ, United Kingdom. E-mail ibw20@cam.ac.uk
2007 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/HYPERTENSIONAHA.107.089391
228
Wallace et al
ISH (mean age: 686 years; range: 57 to 79 years), 30 older
aged-matched control subjects (mean age: 655 years; range: 57 to
74 years), and 48 young healthy control subjects (mean age: 379
years; range: 16 to 51 years). ISH was defined as SBP 140 mm Hg
and DBP 90 mm Hg (on 3 occasions) as stated by the British
Hypertension Society.15 Individuals in the 2 control groups were free
from CV risk factors, including hypertension, and were not receiving
any medication. The local ethics committee approved the study, and
all of the participants gave written, informed consent. The procedures followed were in accordance with institutional guidelines and
the Declaration of Helsinki.
Protocol
All of the studies were conducted in a quiet, temperature-controlled
room. Subjects were asked to attend fasting after having omitted any
229
Statistical Analysis
This study was powered (80%) to identify a 20% difference in FMD
assuming an average value of 51.8% (P0.05). Differences in
baseline characteristics, measures of blood pressure, endothelial
function, and arterial stiffness between the 3 groups were analyzed
using 1-way ANOVA. Posthoc analyses were then conducted using
the Bonferroni correction between 2 specific groups: patients with
ISH versus older control subjects and older control subjects versus
young control subjects. A P0.05 was considered significant.
Multiple linear regression was undertaken using the enter approach
with SPSS 12.02 and included all of the parameters with a univariate
correlation with the dependent variable and any known or likely
confounders. All of the data were presented as meansSD, except
for the variables that are skewed, in which case, values are represented as medians (interquartile range). C-reactive protein (CRP)
was log transformed for correlation analyses, because it is not
normally distributed. aPWV was corrected for mean arterial pressure
(MAP) using linear regression.
Results
The baseline characteristics of the 3 groups are shown in
Table 1. Of the subjects with ISH, 15 were on no treatment,
2 were receiving monotherapy with bendrofluazide, and 1
was taking a calcium channel blocker. The remainder of the
ISH group were on combination therapy, which included a
thiazide (n4), an angiotensin-converting enzyme inhibitor/
angiotensin II receptor subtype 1 antagonist (3), a -blocker
(4), and a calcium channel blocker (2). Other medications
included aspirin (2), thyroxine (1), and lansoprazole (1).
There was no difference in age between the 2 older groups.
Triglycerides were significantly higher in the older group
compared with the young control subjects. There were no
other significant differences in the baseline demographics
(Table 1).
230
Hypertension
TABLE 1.
July 2007
Baseline Demographics
Patients With ISH
(n35)
Overall ANOVA
Age, y
686
655
379*
0.0001
Male/female, n
21/14
16/14
21/27
Weight, kg
78.712.7
76.312.3
74.617.8
0.4
Height, m
1.700.11
1.690.10
1.700.10
0.8
Parameter
Cholesterol, mmol/L
5.21.2
5.21.2
4.80.8
0.1
HDL, mmol/L
1.420.45
1.350.55
1.540.40
0.2
LDL, mmol/L
2.980.90
3.080.79
2.670.85
0.1
Triglycerides, mmol/L
1.871.05
2.131.27
1.350.84*
0.006
Glucose, mmol/L
5.63.5
5.31.4
4.40.7
CRP, mg/L
0.1
0.03
Smokers, n
Values are expressed as meansSD or number, except for variables that were skewed, in which case the values are represented
as median (interquartile range). LDL indicates low-density lipoprotein; HDL, high-density lipoprotein. One-way ANOVA was used to
identify significance between the groups; patients with ISH vs older control subjects; posthoc analyses were conducted using the
Bonferroni method; patients with ISH vs older control subjects; patients with ISH vs older control subjects.
*P0.05, older and young control subjects.
P0.05, patients with ISH vs older control subjects.
Regression Analyses
Data from all of the subjects were then combined. Using
univariate analysis, peripheral PP and central PP (Figure 1)
TABLE 2.
Discussion
Both endothelial function and arterial stiffness are considered
surrogate measures of CV disease and future risk. Interestingly, a number of factors known to impair endothelial
vasomotor function11,18 are also associated with increased
Overall ANOVA
14713*
12813
12010
0.0001
809
788
768
0.06
14712*
12612
11711
0.0001
Parameter
799
767
728
0.001
10211*
937
859
0.0001
6811*
5010
459
0.0001
6112
6511
6511
13713*
11610
10410
0.0001
8110
777
729
0.0001
0.3
Values represent meanSD. One-way ANOVA was used to identify significance between the groups. Posthoc analyses were
conducted using the Bonferroni method.
*P0.01, patients with ISH vs older control subjects.
P0.01, P0.05, older vs young control subjects.
Wallace et al
TABLE 3.
231
Parameter
Overall ANOVA
Supine AP, mm Hg
177*
115
45
0.0001
Supine AIa, %
329
278
1413
0.0001
9.591.97
8.811.97
6.531.30
0.0001
aPWV, m/s
9.652.56
8.260.85
7.091.01
0.0001
8.660.58*
8.190.39
7.800.44
0.0001
4.580.87
4.180.81
3.890.72
0.001
20.313.7
18.510.2
14.28.34
FMD response, %
2.671.64*
4.793.16
6.942.7
0.0001
GTN response, %
6.443.60
8.624.69
9.495.27
0.02
0.4
Values represent meanSD. One-way ANOVA was used to identify significance among the 3 groups. Posthoc analyses were
conducted using the Bonferroni method.
*P0.01, patients with ISH vs older control subjects.
P0.01, older control vs young control subjects.
P0.05, older control vs young control subjects.
232
Hypertension
July 2007
Perspectives
We have shown for the first time that aPWV is independently
associated with endothelial function in patients with ISH.
These findings compliment previous observations suggesting
that local endothelium-derived factors contribute to increased
arterial stiffness and, therefore, to the development of CV risk
factors, such as ISH. This may have important implications
for the management of patients with ISH, because improving
NO bioavailability may reduce arterial stiffness, therefore,
reducing CV risk.
Sources of Funding
S.M.L.W., Y., C.M.M., A.D.B., J.R.C., and I.B.W. received grants
from the British Heart Foundation. K.M.M-P. and I.B.W. have
received grants from GlaxoSmithKline. S.M.L.W. holds a British
Heart Foundation studentship. I.B.W. is a British Heart Foundation
WE Parkes Senior Clinical Fellow. C.M.M. holds a British Heart
Foundation Intermediate Fellowship. This work was performed in a
British Heart Foundationsponsored vascular research laboratory at
Addenbrookes Hospital, Cambridge, United Kingdom.
Disclosures
None.
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