original contributions
See reviewer commentary page 1193
Association of Blood Pressure Control and Metabolic
Syndrome With Cardiovascular Risk in Elderly
Japanese: JATOS Study
Yuhei Kawano1, Toshio Ogihara2, Takao Saruta3, Yoshio Goto4 and Masao Ishii5
Background
The impact of the metabolic syndrome (MS) on cardiovascular events
in elderly subjects has not been clarified. We hypothesized that the
impact differs between patients with and without strictly controlled
blood pressure (BP) and also between early elderly (<75 years) and
late (≥75 years) elderly patients.
Methods
Elderly hypertensive patients (65–85 years old) were randomly
assigned to strict (target systolic BP <140 mm Hg) or mild (140–
159 mm Hg) BP target, and were treated for 2 years with efonidipine-
based regimen. MS was defined according to the National
Cholesterol Education Program Adult Treatment Panel III criteria,
except for the use of body mass index (BMI) ≥25 kg/m2 instead of
waist circumference. Primary endpoint was combined incidence
of cardiovascular and renal events. Data were obtained from 2,865
patients.
Results
The prevalence of MS was 31.4%. The incidence of primary endpoint
in patients with and without MS was 4.0% and 3.1%, respectively.
The benefit of antihypertensive treatment in elderly patients
with hypertension is well documented,1–3 and the beneficial
effect has also been shown in very old subjects.4 However, the
implication of lowering systolic blood pressure (SBP) below
140 mm Hg has not been clearly shown in clinical trials. The
Japanese Trial to Assess Optimal Systolic Blood Pressure in
Elderly Hypertensive Patients (JATOS) compared the thera-
peutic effects of strict treatment to reduce SBP to <140 mm Hg
with that of mild treatment to maintain SBP at 140–160 mm Hg
over a period of 2 years using efonidipine hydrochloride, a
long-acting calcium antagonist, in elderly patients with essen-
1Division of Hypertension and Nephrology, National Cerebral and
Cardiovascular Center, Osaka, Japan; 2Department of Geriatric Medicine,
Osaka University Graduate School of Medicine, Osaka, Japan; 3Department of
Internal Medicine, School of Medicine, Keio University, Tokyo, Japan;
4Japan Physicians Association, Tokyo, Japan; 5Yokohama City University
and Yokohama Seamen’s Insurance Hospital, Yokohama, Japan.
Correspondence: Yuhei Kawano (ykawano@hsp.ncvc.go.jp)
Received 14 December 2010; first decision 23 January 2011; accepted 30 June 2011.
© 2011 American Journal of Hypertension, Ltd.
1250 november 2011 | VOLUME 24 NUMBER 11 | 1250-1256 | AMERICAN JOURNAL OF HYPERTENSION
nature publishing group
MS was a significant risk factor for cardiovascular events in patients
<75 years old (adjusted hazard ratio (HR) 2.17, P = 0.01), but not in
patients ≥75 years old (adjusted HR 0.98, P = 0.94). In patients with
MS, the event rate was significantly lower with strict treatment than
with mild treatment among patients aged <75 years (P = 0.0006) but
not in those aged ≥75 years (P = 0.82).
Conclusions
MS was associated with cardiovascular risk in elderly hypertensive
patients <75 years old, and strict BP control was beneficial for those
with MS. However, MS and intensive control of BP may have little
effect on cardiovascular events in elderly patients ≥75 years old.
Keywords: aged; blood pressure; calcium antagonist;
cardiovascular disease; hypertension; metabolic syndrome
American Journal of Hypertension, advance online publication 4 August 2011;
doi:10.1038/ajh.2011.138
tial hypertension.5,6 The incidence of cardiovascular and renal
events was similar in both groups, however, the incidence of
the primary endpoint tended to be lower with strict treatment
than with mild treatment in younger (65–74 years old) patients,
whereas the opposite trend was observed in older (75–85 years
old) patients. The interaction between age and treatment for
the primary endpoint was statistically significant.
The metabolic syndrome (MS) is a complex of abdominal obes-
ity, hypertension, impaired glucose tolerance, and dyslipidemia,
and is recognized to confer high cardiovascular risk.7–10 The car-
diovascular risk associated with MS has been observed in mid-
dle-aged and elderly populations,11–15 as well as in hypertensive
patients.16,17 It has been suggested that strict control of BP substan-
tially reduces the risk of coronary events in patients with MS.18
However, the benefit of antihypertensive treatment on car-
diovascular outcomes in elderly patients with MS is not clear.
It is also unclear whether the impact of MS on cardiovascular
disease is the same in early elderly (<75 years) and late elderly
(≥75 years) subjects with hypertension. We hypothesized that
the impact of MS on cardiovascular events differs between
Metabolic Syndrome in Elderly Patients original contributions

patients with and without strictly controlled BP and also

Table 1 | Clinical characteristics of patients with and without
between early elderly and late elderly patients under antihy-
metabolic syndrome (MS)
pertensive treatment. In this study, we evaluated the impact of
MS Non-MS
MS in relation to BP control and age on cardiovascular events Variables (n = 900) (n = 1,965) P
in elderly hypertensive patients as a sub-analysis of the JATOS.
Male (%) 308 (34.2%) 829 (42.2%) <0.0001

Methods Age, years 73.0 ± 5.2 73.6 ± 5.3 0.005

Study design Systolic blood pressure, mm Hg 172 ± 10 172 ± 10 0.92
Outline of the JATOS: The design of the JATOS has been Diastolic blood pressure, mm Hg 89 ± 10 90 ± 9 0.03
reported in more detail elsewhere.5,6 In brief, the JATOS was Body mass index, kg/m2 25.7 ± 3.3 22.6 ± 3.0 <0.0001
a prospective, randomized, open-label study with blinded Fasting blood glucose, mg/dl 114.8 ± 28.6 98.1 ± 16.8 <0.0001
assessment of endpoints. It was designed to compare the effects HDL-cholesterol, mg/dl 47.5 ± 12.0 60.7 ± 14.6 <0.0001
of 2 years of strict antihypertensive treatment to maintain SBP
Triglyceride, mg/dl 191.1 ± 102.9 109.4 ± 51.5 <0.0001
<140 mm Hg with those of mild treatment to maintain SBP
LDL-cholesterol, mg/dl 127.4 ± 33.1 121.2 ± 30.6 <0.0001
at 140–160 mm Hg in elderly patients aged 65–85 years with
essential hypertension (baseline SBP ≥160 mm Hg). Treated Enlarged heart or LVH (%) 506 (56.2%) 918 (46.7%) <0.0001
hypertensive patients could be enrolled without withdrawing History of cerebrovascular 39 (4.3%) 81 (4.1%) 0.79
treatment. The baseline drug was efonidipine hydrochloride, disease (%)
a long-acting dihydropyridine calcium antagonist. The daily History of cardiac 23 (2.6%) 49 (2.5%) 0.92
and vascular disease (%)
doses of efonidipine were 20–60 mg. Other classes of antihy-
pertensive drugs were added if allocated target BP was not Renal diseasea (%) 138 (15.3%) 231 (11.8%) 0.008
reached with efonidipine monotherapy. Written informed con- Diabetes mellitus (%) 199 (22.1%) 128 (6.5%) <0.0001
sent was obtained from all subjects before the run-in period. Dyslipidemia (%) 689 (76.6%) 807 (41.1%) <0.0001
The study protocol was approved by the ethics committee Current smoking (%) 103 (11.4%) 292 (14.9%) 0.01
Japan Physicians Association and by the executive committee. Prior antihypertensive 502 (55.8%) 973 (49.5%) 0.002
Subjects and endpoints: Overall, 4,418 patients were ran- treatment (%)
domly assigned to receive either strict treatment (n  =  2,212) Data are expressed as means ± s.d., or n (percentage) of patients.
or mild treatment (n  =  2,206). The primary endpoint was HDL, high-density lipoprotein; LDL, low-density lipoprotein; LVH, left ventricular
hypertrophy.
the combined incidence of cerebrovascular disease (cerebral aProteinuria or elevated serum creatinine (men ≥1.3, women ≥1.2 mg/dl).
hemorrhage, cerebral infarction, transient ischemic attack,
and subarachnoid hemorrhage), cardiac and vascular disease
(myocardial infarction, angina pectoris requiring hospitaliza- (25 kg/m2) was according to the criteria for obesity disease in
tion, heart failure, sudden death, dissecting aneurysms of the Japan.20 Therefore, the definition of MS required three or more
aorta, and occlusive arterial disease), and renal failure (dou- of the following five disorders: (i) BMI ≥25 kg/m2, (ii) serum
bling of the serum creatinine concentration with the reached triglyceride ≥150 mg/dl, (iii) high-density lipoprotein cho-
level of serum creatinine ≥1.5 mg/dl). Patients with recent lesterol <40 mg/dl in men and <50 mg/dl in women, (iv) SBP
stroke or myocardial infarction, severe congestive heart failure, ≥130 mm Hg and/or diastolic BP ≥85 mm Hg, and (v) fasting
severe arrhythmia, occlusive arterial disease, overt renal dys- blood glucose ≥110 mg/dl.
function (serum creatinine of 1.5 mg/dl or higher), or poorly
controlled diabetes mellitus were excluded from the study. Statistical analysis. The incidence of primary endpoint was cal-
Baseline examination and follow-up: At the start of the study, culated as a proportion of subjects who experienced the end-
the patients were evaluated for the presence of cardiovascular point during the trial. Variables are expressed as percentages or
risk factors, such as smoking, diabetes, dyslipidemia, obesity, means ± s.d. We compared the means of continuous variables
family history of premature cardiovascular disease, history of using Welch’s t test and proportions using χ2 tests. Bonferroni’s
cerebrovascular disease, enlarged heart/cardiomegaly, history method was used for multiple comparisons. Difference in the
of cardiac or vascular diseases, and renal damage. The enlarged influence of MS between subgroups for the incidence was
heart was defined as cardiothoracic ratio of ≥50% on chest assessed with the Breslow-Day test.21 To assess differences in
X-ray film, and left ventricular hypertrophy was diagnosed the event-free survival, hazard ratios (HRs) and corresponding
according to Sokolow-Lyon criteria on electrocardiogram. 95% confidence intervals (CIs) were estimated with the use of
Complete baseline and follow-up data were obtained from the Cox proportional hazards method. All statistical tests were
2,865 patients, and were used for this sub-analysis. two-sided, and the significance level was set at 5%.
Diagnosis of MS: In the JATOS, the diagnosis of MS was
made according to the National Cholesterol Education Results
Program Adult Treatment Panel III criteria,19 but body mass Clinical characteristics of patients
index (BMI) was used instead of waist circumference because At baseline, 31.4% of patients met the diagnostic criteria for
waist circumference was not measured. The cut off level of BMI MS (Table 1). Patients with MS were more likely to be women,

AMERICAN JOURNAL OF HYPERTENSION | VOLUME 24 NUMBER 11 | november 2011 1251

original contributions Metabolic Syndrome in Elderly Patients

Table 2 | Baseline clinical characteristics of patients with and without metabolic syndrome (MS) according to treatment received
MS Non-MS
Strict treatment Mild treatment Strict treatment Mild treatment
Variables (n = 457) (n = 443) P (n = 988) (n = 977) P
Male (%) 159 (34.8) 149 (33.6) 0.71 436 (44.1) 393 (40.2) 0.08
Age, years 72.8 ± 5.1 73.3 ± 5.2 0.14 73.7 ± 5.3 73.5 ± 5.2 0.32
Systolic blood pressure, mm Hg 172 ± 9 172 ± 10 0.77 172 ± 10 172 ± 10 0.31
Diastolic blood pressure, mm Hg 89 ± 10 89 ± 10 0.63 90 ± 9 90 ± 9 0.69
Body mass index, kg/m2 25.8 ± 3.2 25.6 ± 3.5 0.28 22.5 ± 3.0 22.6 ± 3.1 0.21
Fasting blood glucose, mg/dl 114.7 ± 29.0 114.9 ± 28.2 0.90 98.8 ± 17.4 97.4 ± 16.1 0.07
HDL-cholesterol, mg/dl 47.6 ± 12.1 47.3 ± 11.8 0.66 60.4 ± 14.3 61.1 ± 14.9 0.31
Triglyceride, mg/dl 195.0 ± 105.6 187.0 ± 100.0 0.25 109.8 ± 54.7 109.1 ± 48.2 0.76
LDL-cholesterol, mg/dl 127.0 ± 32.9 127.9 ± 33.4 0.69 120.8 ± 30.4 121.7 ± 30.7 0.50
Enlarged heart or LVH (%) 256 (56.0) 250 (56.4) 0.90 450 (45.5) 468 (47.9) 0.30
History of cerebrovascular disease (%) 12 (2.6%) 27 (6.1%) 0.01 43 (4.4%) 38 (3.9%) 0.61
History of cardiac and vascular disease (%) 14 (3.1%) 9 (2.0%) 0.33 30 (3.0%) 19 (1.9%) 0.12
Renal diseasea (%) 67 (14.7%) 71 (16.0%) 0.57 117 (11.8%) 114(11.7%) 0.90
Diabetes mellitus (%) 105 (23.0%) 94 (21.2%) 0.53 68 (6.9%) 60 (6.1%) 0.51
Dyslipidemia (%) 360 (78.8%) 329 (74.3%) 0.11 396 (40.1%) 411 (42.1%) 0.37
Current smoking (%) 59 (12.9%) 44 (9.9%) 0.16 148 (15.0%) 144 (14.7%) 0.88
Prior antihypertensive treatment (%) 254 (55.6%) 248 (56.0%) 0.90 476 (48.2%) 497 (50.9%) 0.23
Data are expressed as means ± s.d., or n (percentage) of patients.
HDL, high-density lipoprotein; LDL, low-density lipoprotein; LVH, left ventricular hypertrophy.
aProteinuria or elevated serum creatinine (men ≥1.3, women ≥1.2 mg/dl).

slightly younger, and showed comparable SBP but lower
diastolic BP, higher low-density lipoprotein cholesterol, and
higher prevalence of left ventricular hypertrophy compared
with patients without MS. History of cardiovascular disease
was similar between the two groups, but renal disease was
more common in patients with MS than in patients without
MS. The prevalence of smokers was lower and that of prior
antihypertensive treatment was higher in patients with MS
than in those without MS.
Table  2 shows the clinical characteristics of patients with
and without MS in the strict and mild treatment groups. In
patients with MS, there were no significant differences in sex,
age, baseline BP, BMI, metabolic parameters, and other risk
factors, except for history of cerebrovascular disease between
the strict and mild control groups. In patients without MS,
these parameters were not significantly different between the
two groups.
BP control during the treatment period
BP decreased in both treatment groups, and average BP was
controlled within the target levels (Figure  1). The difference
in SBP and diastolic BP between the two groups was signifi-
cant after 3 months and thereafter. In patients with MS, BP
after 24 months was significantly lower in the strict treatment
group (137 ± 13/75 ± 10 mm Hg) than in the mild treatment
group (146  ±  11/78  ±  9 mm Hg) (P < 0.0001). Similarly, in
patients without MS, BP was significantly lower in the strict
treatment group (135  ±  11/74  ±  9 mm Hg) than in the mild
treatment group (146 ± 11/79 ± 9 mm Hg) (P < 0.0001). At the
end of study, antihypertensive drugs other than efonidipine
were more frequently used in the strict treatment group than
in the mild treatment group (P < 0.001), but the number of
antihypertensive drugs was not different between the MS and
non-MS groups (percentage of combination therapy: strict
treatment MS group 37%, non-MS group 34% (P = 0.18), mild
treatment MS group 28%, non-MS group 27% (P  =  0.19)).
The rate of discontinuation from the study was 20% in the MS
group and 18% in the non-MS group. This difference was of
borderline significance (P = 0.06). It was not different between
the strict and mild control groups (P = 0.90).
Primary endpoint
The incidence of the primary endpoint in the total popula-
tion, in patients with MS, and in those without MS is shown
in Table 3. There was no significant difference in the incidence
of primary endpoint as well as its components between the MS
group and non-MS group. The impact of MS was also not sig-
nificant both in men and women. However, in the mild treat-
ment group, the incidence of the primary endpoint was higher
in patients with MS (5.2%) than in patients without MS (2.5%)
(P = 0.008). In the strict control group, the difference was not
significant (2.8% vs. 3.7%, P  =  0.38). There was a significant
difference in the influence of MS between the treatment groups
in terms of the primary endpoint (P = 0.02).
The incidence of the primary endpoint was higher in patients
≥75 years old than in those <75 years old (P = 0.003). Table 4

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Metabolic Syndrome in Elderly Patients original contributions

a Patients with MS
180

160
* * * * * * * *
Blood pressure (mm Hg) Mild treatment
140 Strict treatment

120

100

80
* * * * * * * * Mild treatment
Strict treatment

60

0 3 6 9 12 15 18 21 24 (Months)
Mild treatment (n) 443 394 374 350 343 326 314 294 296
Strict treatment (n) 457 412 381 372 359 340 336 325 303

b Patients without MS
180

160
Blood pressure (mm Hg)

* * * * * * * * Mild treatment
140 Strict treatment

120

100

* * * * * * * * Mild treatment
80
Strict treatment
60

0 3 6 9 12 15 18 21 24 (Months)
Mild treatment (n) 977 871 832 800 788 736 727 710 704
Strict treatment (n) 988 883 862 816 804 762 747 718 709

*P < 0.05 vs·strict treatment group

Figure 1 | Time course of changes in blood pressure in the strict control group and the mild control group among patients (a) with or (b) without metabolic
syndrome (MS). *P < 0.05 strict vs. mild treatment group.

Table 3 | Incidence of the primary endpoint and its components according to treatment in patients with and without metabolic
syndrome (MS)
Strict treatment group Mild treatment group Overall
MS Non-MS MS Non-MS MS Non-MS
(n = 457) (n = 988) Pa (n = 443) (n = 977) P (n = 900) (n = 1965) P Pb
Primary endpoint 13 (2.8) 37 (3.7) 0.38 23 (5.2) 24 (2.5) 0.008 36 (4.0) 61 (3.1) 0.22 0.02
Cerebrovascular disease   6 (1.3) 26 (2.6) 0.11 13 (2.9) 15 (1.5) 0.08 19 (2.1) 41 (2.1) 0.97 0.02
Cardiac and vascular disease   5 (1.1)   8 (0.8) 0.59   8 (1.8)   6 (0.6) 0.04 13 (1.4) 14 (0.7) 0.06 0.32
Renal failure   2 (0.4)   3 (0.3) 0.69   2 (0.5)   3 (0.3) 0.67   4 (0.4)   6 (0.3) 0.56 0.99
Results are expressed as n (percentage) of patients. Primary endpoint: the combined incidence of cerebrovascular disease , cardiac and vascular disease, and renal failure.
aMS vs. without MS. bInteraction between the MS status and the treatment group.

shows the incidence of the primary endpoint in younger and ment group (P = 0.003), but not in the strict treatment group
older patients in relation to MS. In patients <75 years old, the (P = 0.84). This relationship in the mild treatment group was
incidence was significantly higher in those with MS than in evident in patients <75 years old, but was not significant in
those without MS. The association of MS with cardiovascular patients ≥75 years old (Figure 2). It was not observed in either
events in this age group was highly significant in mildly treated age group of strictly treated patients. Regarding the influence
patients but was not significant in strictly treated patients. On of each component of MS (other than BP), high blood glu-
the other hand, in patients ≥75 years old, there was no difference cose was significantly associated with the cardiovascular out-
in the incidence of events between those with and those without come (HR 1.63, 95% CI: 1.06–2.50, P = 0.03). The HR of BMI
MS either in the strict treatment group or mild treatment group. (0.92, 95% CI: 0.59–1.44, P  =  0.72), high triglyceride (1.13,
A significant trend was observed between the number of 95% CI: 0.72–1.78, P  =  0.59), and low high-density lipopro-
MS components and the incidence of events in the mild treat- tein cholesterol (1.28, 95% CI: 0.81–2.04, P  =  0.29) was not

AMERICAN JOURNAL OF HYPERTENSION | VOLUME 24 NUMBER 11 | november 2011 1253

original contributions Metabolic Syndrome in Elderly Patients

Table 4 | Incidence of the primary endpoint in patients with and without metabolic syndrome (MS) according to treatment and age
Strict treatment group Mild treatment group Overall
MS Non-MS Pa MS Non-MS P MS Non-MS P
<75 years old, n 291 558 271 569 562 1127
  Primary endpoint, n (%) 5 (1.7) 13 (2.3) 0.56 16 (5.9) 9 (1.6) 0.0006 21 (3.7) 22 (2.0) 0.03
≥75 years old, n 166 430 172 408 338 838
  Primary endpoint, n (%) 8 (4.8) 24 (5.6) 0.71 7 (4.1) 15 (3.7) 0.82 15 (4.4) 39 (4.7) 0.87
Pb 0.10
aMS vs. without MS. bInteraction between the MS status and the age group on the primary endpoint.

P = 0.52 P = 0.0003 P = 0.84 P = 0.53

(%) (%) (%) (%)
8 8 7.5 8 8 7.4
6.6
6.1
6 6 6 6
5.1
4.7
Event rate

4.0
4 4 4 4 3.6 3.8
3.1 3.2
2.5
2.1
2 1.7 2 2 2
1.1
1.0

0 0 0 0
Number of
1 2 3 ≥4 1 2 3 ≥4 1 2 3 ≥4 1 2 3 ≥4
components
n = 260 298 198 93 281 288 178 93 234 196 100 66 222 186 118 54
Strict treatment Mild treatment Strict treatment Mild treatment
Patients <75 years old Patients ≥75 years old

Figure 2 | Number of metabolic syndrome components and the incidence of the primary endpoint according to age of patients and treatment received. P values
mean “P values for trend.” Primary endpoint: the combined incidence of cerebrovascular disease, cardiac and vascular disease, and renal failure.

Patients
n
Non MS/MS P* 95%CI
treatment group (HR: 3.80), but not in the strict treatment
group (HR: 0.99). In patients ≥75 years old, the presence of MS
0.01 1.17–4.02
Patients <75 years old 1,127/562 did not affect cardiovascular or renal outcomes (adjusted HR:
Strict treatment 558/291 0.99 0.35–2.85
0.98). MS was not associated with these outcomes in either the
Mild treatment 569/271 0.002 1.65–8.74 strict (HR: 0.94) or mild (HR: 1.00) treatment groups.

Patients ≥75 years old 0.94 0.53–1.79

838/338
Strict treatment 430/166
Mild treatment
408/172
0.5 21 4 8
HR 95%CI
Adjusted for sex, smoking, history of cerebrovascular disease, history
of cardiac and vascular disease, renal disease, LDL-cholesterol
Figure 3 | Impact of metabolic syndrome (MS) on the incidence of the
primary endpoint in patients aged <75 or ≥75 years old with respect to the
intensity of antihypertensive treatment. CI, confidence interval; HR, hazard
ratio; LDL, low-density lipoprotein.
statistically significant. The number of MS components did
not correlate with the level of baseline BP or pulse pressure
(1: 171  ±  12/89  ±  10 mm Hg, 2: 171  ±  13/89  ±  10 mm Hg, 3:
171 ± 12/89±11 mm Hg, 4: 171 ± 12/88±11 mm Hg).
The impact of MS on the incidence of primary endpoint was
also evaluated using Cox’s model with adjustment for poten-
tial cofounders (Figure 3). The impact of MS was significant in
patients <75 years old (adjusted HR: 2.17 vs. the non-MS pop-
ulation). This association was particularly evident in the mild
Discussion
0.88 0.42–2.12 In this sub-analysis of the JATOS, the risk of the composite
0.998 0.40–2.50
of cardiovascular and renal events was significantly higher in
hypertensive patients aged 65–74 years with MS than in those
without MS. However, in patients aged 75–85 years, there was
no difference in the incidence of events between those with
MS and those without MS. In terms of the level of BP, the inci-
dence of the primary endpoint was not significantly different
between patients with MS and those without MS in the strict
treatment group (target SBP <140 mm Hg). On the other hand,
the incidence of the primary endpoint was higher in patients
with MS than in those without MS in the mild treatment
group (target SBP 140–159 mm Hg). These results suggest that
age and BP influence the impact of MS as a cardiovascular risk
factor in elderly hypertensive patients.
MS is common in middle-aged and elderly subjects, and the
prevalence of MS in elderly people has been reported to range
from 30% to 50% in population-based studies.11–15,22,23 In the
JATOS, the prevalence of MS was about 30% of participants
with hypertension. The prevalence of MS may vary according
to the diagnostic criteria, and we used the modified criteria of

1254 november 2011 | VOLUME 24 NUMBER 11 | AMERICAN JOURNAL OF HYPERTENSION

Metabolic Syndrome in Elderly Patients
the National Cholesterol Education Program Adult Treatment
Panel III with BMI instead of waist circumference. The rela-
tively low prevalence of MS among the JATOS participants
who had high BP can be explained by the smaller number of
overweight and obese subjects compared with western and
other Asian populations.
The cardiovascular risk associated with MS has been
observed in middle-aged subjects and in elderly popula-
tions.11–15 According to a recent meta-analysis, the presence
of MS is associated with a twofold increase in cardiovascu-
lar outcomes and a 1.5-fold increase in all-cause mortality.11
Regarding elderly population, the Health, Aging, and Body
Composition study showed that patients with MS had signifi-
cantly higher incidence of ischemic heart disease (HR 1.56).12
In the Cardiovascular Health Study, there were 20–30% more
cardiovascular events among elderly participants with MS than
in those without MS.13 Wang et al. reported that MS, defined
by various criteria, was significantly associated with incident
stroke (HR: 1.5–1.7) in Finnish subjects aged 65–74 years.14
Several other studies have also showed associations between
MS and cardiovascular disease in elderly subjects.15,22,23
However, MS did not significantly increase cardiovascu-
lar risk in some studies. In a sub-analysis of the Prospective
Study of Pravastatin in the Elderly at Risk, no association was
found between MS and cardiovascular risk (HR: 1.07) in sub-
jects aged >70 years with a history of vascular disease or at
high risk for vascular disease.24 In the British Regional Heart
Study, the association was weak and not significant (relative
risk 1.27) among subjects aged 60–79 years.24 In the JATOS,
the impact of MS on composite cardiovascular and renal out-
come was not significant among elderly hypertensive patients
although patients with MS had a 29% higher risk for the pri-
mary endpoint. Reasons for the discrepancy among the stud-
ies are not clear, however, the characteristics of study subjects
such as age, race and clinical background may be responsible
for the differences. Taken together, it appears that the pres-
ence of MS modestly increases cardiovascular risk in elderly
population.
The influence of age on the impact of MS on cardiovascular
disease has not been investigated in elderly populations. Our
findings suggest that the impact of MS on cardiovascular dis-
ease is apparent in subjects aged <75 years old, but diminishes
beyond 75 years of age. In a recent cohort study of very old
(mean age 85 years) high-risk subjects, low BMI, low diasto-
lic BP, low total and high-density lipoprotein cholesterol, and
high insulin sensitivity were associated with total mortality.25
Further studies are required to clarify the significance of MS in
the very old population.
In this study, the incidence of the primary endpoint was not
significantly different between patients with MS and those
without MS in the strict treatment group, but the incidence
was higher in patients with MS than in patients without MS in
the mild treatment group. In terms of the number of MS com-
ponents and the primary endpoint, the association was not
significant in the strict treatment group, but cardiovascular
and renal events increased linearly with increasing number of
AMERICAN JOURNAL OF HYPERTENSION | VOLUME 24 NUMBER 11 | november 2011 1255
original contributions
components of MS in the mild treatment group. These results
indicate that MS has a marked influence when the control of
BP is insufficient, but not under strict BP control in elderly
hypertensive patients. However, the benefit of strict control
of SBP to <140 mm Hg in patients with MS was evident in
patients aged <75 years, but not in those aged ≥75 years.
The mechanism(s) of the diverse effects of the strict BP con-
trol on the cardiovascular risk between age groups or MS sta-
tuses cannot be clarified from this study. However, it has been
shown that the relative risk of high BP on cardiovascular out-
come is remarkable in middle-aged and early elderly subjects
but is attenuated in late elderly subjects.26 Therefore, the effect
of strict BP control may be weak in late elderly patients with
hypertension. Although our study supports the importance of
BP control for elderly hypertensive patients with MS, further
studies are needed to determine appropriate treatment goals.
There are several limitations in this study. First, the MS pop-
ulation in the present study consisted of hypertensive patients
with initial SBP ≥160 mm Hg. This characteristic of the study
subjects may influence the prevalence of MS and the incidence
of cardiovascular disease in the JATOS. The generalizability
of the findings from JATOS is also limited because it is not a
community-based study. Second, BMI ≥25 kg/m2 was substi-
tuted for waist circumference as a component of MS. Although
BMI is recognized as a good index of obesity, waist circum-
ference may be better index of abdominal obesity and related
cardiovascular diseases. Third, the study was performed in
Japanese subjects, in whom cardiovascular risk is relatively low
and stroke accounts for a higher proportion of the composite
endpoint than would be expected in other ethnic populations.
Fourth, the treatment and follow-up period in the JATOS
might not be sufficient to determine the influence of MS or
the effect of antihypertensive therapy on the outcomes. Finally,
the study was not designed to address the hypothesis tested in
this post hoc, subgroup analysis. Further studies with longer
follow-up periods may be required to confirm the findings of
this study.
In conclusion, the present study showed that the cardiovas-
cular risk associated with MS was evident in elderly patients
with hypertension aged <75 years, but not in those aged ≥75
years. The increased cardiovascular risk associated with MS
was apparent when SBP was controlled mildly but not under
strict SBP control, although this difference was not observed in
patients aged ≥75 years. Therefore, strict control of BP appears
to be desirable for elderly hypertensive patients with MS,
particularly for those <75 years old. However, the benefit of
aggressive antihypertensive therapy is not obvious for patients
aged ≥75 years, even if they have MS.
Acknowledgments: Japan Physicians Association and Japanese Society of
Hypertension supported this study. Shionogi & Co., Ltd., Japan supplied
research fund. We thank all the members and researchers of the JATOS
group.
Disclosure: Y.K., T.O., and T.S. received honorarium for lectures from several
pharmaceutical companies including Shionogi & Co., Ltd. Y.G. and M.I.
declared no conflict of interest.
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