(Hypertension. 2001;37:1083.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Silent ST Depression and Cardiovascular End-Organ Damage in Newly Found, Older Hypertensives
Presented in part at the Fourteenth Scientific Meeting of the American Society of Hypertension, New York, NY, May 1999.
From the Department of Cardiology/Thoraxcenter (W.F.T., J.F.M., H.J.G.M.C.), the Department of Internal Medicine (A.J.S., P.A.d.G.), and the Department of General Practice (B.M.-d.J.), University Hospital Groningen; and Groningen Hypertension Service (J.F.M., A.J.S., P.A.d.G., F.H.S., B.M.-d.J.), Groningen, The Netherlands.
Correspondence to W.F. Terpstra, MD, Department of Cardiology/Thoraxcenter, University Hospital Groningen, Hanzeplein 1, PO Box 30.001, 9713 GZ Groningen, The Netherlands. E-mail w.f.terpstra{at}castel.nl
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Abstract |
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Abstract—In hypertension, both reduced vascular supply and increased cardiac demand contribute to the development of (silent) myocardial ischemia. Our aim was to determine the prevalence of ST-segment depression and to analyze contributing factors in asymptomatic, previously untreated, older hypertensives. From a population survey, in 184 patients with mild hypertension (4 times systolic blood pressure
160 mm Hg and/or diastolic blood pressure
95 mm Hg), 60 to 75 years of age,
cardiovascular end-organ damage was measured. Episodes
of ST-segment depression were measured by 48-hour ambulatory Holter
monitoring and were observed in 21 hypertensives (12%). They showed a
significantly higher combined far-wall intima-media thickness of
carotid and femoral arteries and more arterial plaques as
measured by B-mode ultrasound compared with hypertensives without ST
depression (0.00098±0.00021 versus 0.00088±0.00016 mm and
5.2±3.7 versus 3.7±2.8 plaques,
P<0.05, respectively), whereas
left ventricular mass index was not different (111±18
versus 104±24 g/m2;
P=0.18, respectively). In
hypertensives with transient ST-segment depression, a significant
relation was found between left ventricular mass and
ischemic burden
(r=0.51,
P=0.02). Approximately 1 of 8
unselected and previously untreated older hypertensives show
asymptomatic ST-segment depression, suggestive of silent
myocardial ischemia. These data suggest that vascular factors
mainly determine the occurrence of ischemic ST-segment
depression and cardiac factors determine the ischemic burden in
older hypertensives.
Key Words: ischemia • hypertrophy, left ventricular • ventricular function, left • elderly • hypertension, secondary
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Silent myocardial ischemia is defined as transient myocardial ischemia in the absence of angina pectoris or other cardiac symptoms. It is frequent among hypertensive patients with or without atherosclerotic coronary disease, even in the absence of epicardial coronary artery disease or left ventricular hypertrophy.1 2 Zehender et al3 observed transient ST-segment depression on Holter monitoring in 33% of 150 middle-aged, ineffectively treated, hypertensive patients without manifest coronary artery disease. The majority of these episodes of transient myocardial ischemia was not associated with symptoms. Hedblad and Janzon4 reported a high incidence of ischemic ST depression of 41% in treated hypertensive men with inadequate blood pressure control. Whether antihypertensive treatment influences the ST-segment depression in hypertension is debatable; without these drug treatment effects, the pathophysiology of ST-segment depression can be studied. To our knowledge, no study reported prevalence of asymptomatic ST-segment depression in a large group of never-treated, hypertensive patients.
Important vascular factors contributing to the occurrence of myocardial ischemia in hypertensive patients include atherosclerotic obstruction of the large coronary arteries and a reduced vasodilatory capacity of the coronary microcirculation caused by arteriolar hypertrophy and endothelial dysfunction. Another factor contributing to the occurrence of myocardial ischemia is the increased myocardial oxygen demand to supply the hypertrophic myocardium as it is seen in hypertension. Both vascular supply and cardiac demand factors reduce the capacity of the coronary circulation to increase myocardial blood flow during stress and therefore reduce the coronary blood flow reserve.
The objective of this study was to determine the prevalence and characteristics of transient ST-segment depression and its relation with cardiovascular end-organ damage as measured by left ventricular mass and large-vessel intima-media thickness (IMT) in previously untreated, older hypertensive patients.
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Methods |
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Patients
Patients with previously untreated mild to moderate hypertension were recruited from a population survey performed in the north of the Netherlands in 2 rural municipalities. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured 4 times at 3 occasions. Patients were included in the study if SBP or DBP was 4 times
160 mm Hg or 95 mm Hg,
respectively, and if they were between 60 and 75 years of age and had
not been treated with antihypertensive drugs. Exclusion criteria were
angina pectoris, manifest coronary artery disease (history of
myocardial infarction, ECG at rest with pathological Q waves, or
ST-segment changes, interpreted by an experienced cardiologist),
secondary hypertension of any cause, current or recent history of
congestive heart failure, hemodynamically significant
valvular heart disease, cardiac arrhythmias, renal
insufficiency, and electrolyte disturbances (serum potassium
<3.0 mmol/L or >6.0 mmol/L). Patients with pacemakers,
bundle-branch block, and office blood pressure >220/115 mm Hg
were excluded. The research protocol was approved by the Medical
Ethical Committee of the University Hospital of Groningen, and
written informed consent was obtained from all
subjects.
Holter Monitoring
All patients underwent 48 hours of Holter monitoring
during unrestricted daily life and were asked to keep a detailed diary
of their activities and symptoms. Ambulatory 48-hour ST-segment
monitoring was performed with a 4-channel ambulatory cardiograph
(Marquette series 8500) with modified leads aVF,
V1, and V5 for the ECG
and the fourth channel to record a 32-Hz time signal. This signal
was used in a phase-locked loop circuit as well as a timer for the AD
converter to correct tape speed irregularities. The ECG was
analyzed on a Marquette XP analyzer (software version
5.8) and reviewed by an experienced analyst and supervised by a
cardiologist, who were both blinded to clinical data. The 1x1x1 rule
according to P.F. Cohn was
applied.5 The criteria to be
studied were horizontal or downsloping ST-segment depression of 0.1
mV. The depression in one of the leads had to last 1 minute to be
scored as an ischemic period. Episodes during postural changes
and/or intraventricular conduction changes as
explanations for ST-segment depression were excluded. When an
ST-segment depression started within 1 minute after the end of the
previous one, it was only recorded as a new one when abrupt changes
in the ST-T shift were excluded. Number and total duration of
ischemic periods, maximal ST depression, and ischemic
burden, defined as total ST depression multiplied by time, were
determined. Ambulatory ECG monitors were hooked up at the end of the
physical examinations, usually between 11
AM and 4
PM, and were removed after
48 hours.
B-Mode Ultrasound Imaging
The B-mode ultrasound imaging of the carotid and the
femoral arterial walls was done with an Acuson 128
(Acuson Corp) ultrasound machine, equipped with a 7.0-MHz L7384 linear
array transducer, by 2 experienced sonographers who were blinded to the
clinical data. The methods used to record and analyze
B-mode ultrasound images have been described in detail
before.6 In short, 10
prespecified segments, 3 from the left and right carotid arteries and 2
of the left and right femoral arteries, were scanned. In the carotid
artery, the arterial segment 1 cm proximal to the carotid
dilation (the common carotid artery), the arterial segment
between the carotid dilation and carotid flow divider (carotid bulb),
and a 1-cm-long arterial segment distal to the flow divider
(internal carotid artery) were measured. In the femoral artery, a
1-cm-long arterial segment proximal to the femoral dilation
(common femoral artery) and a 1-cm arterial segment distal
to the femoral flow divider (superficial femoral artery) were measured.
Of each arterial segment, 5-second real-time image
sequences were stored on S-VHS. B-mode ultrasound video images were
analyzed off-line (S-VHS Panasonic NV-FS 100 HQ; VCR; Sony
GVM-1400 QM multisync monitor; IDEN IVT-7p time base correctors, IPC
80486 personal computer equipped with DT2861 and DT2862 frame
grabbers). Image analysis software was developed in cooperation
with Selzer et al.7 The mean
value of the IMT of the mean far walls of 3 carotid artery segments and
2 femoral artery segments was used for analysis. The IMT of the
far wall was evaluated as the distance between the luminal-intimal
interface and the medial-advential interface. When macrovascular
lesions were obvious and the IMT was not measurable, lesions were
considered plaques. Plaques were scored as a dichotomous variable
in the 10 predefined arterial segments in both the near and
far walls, and the score of plaques was expressed as the total amount
of plaques of all arterial segments. The average plaque
score of all arterial segments per patient was used for
analysis. The measurement error of variation in the population
studied was 0.03 mm for the mean maximum far-wall IMT. The primary
end point of the B-mode ultrasound study was the combined mean far-wall
IMT of the 10 segments of the carotid and femoral
arteries.
Echocardiography
Echocardiographic examinations were
recorded by a single trained operator. An Acuson XP-10
echocardiograph (Acuson Corp) with a 2.5- to 4.0-MHz
transducer was used. Left ventricular dimensions were
measured in 2D mode according to the Penn Convention in the left
lateral decubitus position. Three recordings were made of the
end-diastolic left ventricular wall (LVPW),
interventricular septum (IVS), and left
ventricular end-diastolic diameter (EDD). To
estimate left ventricular mass, the cube formula of
Devereux and Reichek was
used.8 To calculate left
ventricular mass index, the left ventricular
mass was divided by body surface area. For classification of the 4
groups of left ventricular geometry (normal geometry,
concentric remodeling, eccentric left ventricular
hypertrophy [LVH], and concentric LVH), the following
cutoff values were used. LVH was defined as left
ventricular mass index 125
g/m2; increased relative wall thickness
(RWT) was defined as RWT 0.45, as proposed by Koren et
al.9 Systolic wall
stress was determined10
according to the formula
Systolic wall stress
(10dyne/m2) =(1.33 · SBP · LVEDD/2):(IVS+LVPW).
Statistical Analysis
Descriptive statistics and comparisons between groups
were performed with the SPSS statistical package (SPSS for Windows,
version 8.0, SPSS Inc). All descriptive data are expressed as mean±SD.
Equality of variances between groups with or without transient
ST-segment depression were tested with Levene’s test. The independent
t test for equality of means
was used to detect significant differences between the two groups as
appropriate. In the case of categorical variables, the
2 test was used. Changes in heart rate
within patients were tested by a paired
t test. Univariate
analysis of the associations between end-organ damage and
parameters of ST-segment depression were performed with
Pearson correlation coefficients after natural log transformation of
the ST-segment parameters. To identify the determinants of
episodes of ST-segment depression, logistic regression analysis
was used. Clinical baseline variables included age, gender, body
mass index, smoking, total cholesterol, HDL, LDL,
non–insulin-dependent diabetes, SBP and DBP, pulse pressure,
rate-pressure product, systolic wall stress, combined mean
far-wall IMT, average plaque score, and left ventricular
mass index.
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Results |
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Patients
From the population survey, 1969 subjects had their blood pressure taken. A total of 1162 subjects had normal blood pressure, 421 subjects were treated with antihypertensive drugs, 214 subjects were identified as having untreated systolic hypertension, and 172 subjects were identified as having untreated diastolic hypertension. From these 386 untreated subjects, 184 fulfilled the inclusion and exclusion criteria and entered the study. Table 1 shows a comparison between hypertensive subjects with and those without ST-segment depression. The two groups differed with respect to body mass index and pulse pressure but not with respect to age, SBP and DBP, and lipid profile.
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Prevalence of ST-Segment Depression
Recordings of Holter monitoring of adequate
quality could be obtained from 178 patients (53% men), with a
monitoring period of at least 46 hours. Of 6 patients, the quality of
the Holter monitoring was inadequate for analysis. A total of
21 patients (12%) had a total of 97 episodes of significant ST-segment
depression (median, 3.0 episodes per patient; range, 1 to 19). The
prevalence was 9% in women and 13% in men. The duration of the single
episodes was between 1.2 and 17.2 minutes (mean±SD: 4.1±3.3). The
range of total ischemic burden was between 2.5 and 453
mm/min. All patients had sinus rhythm, and no patient was taking
digitalis medication. No patient recorded symptoms such as angina
pectoris, so all ischemic periods were asymptomatic
or at least not likely to be associated with definite symptoms of
angina pectoris.
Circadian Variation in Ischemic
Episodes and Relation to Heart Rate
Circadian variation in the frequency of
ischemic episodes is shown in
Figure 1. Ischemic episodes were nearly absent
during the 6 night hours from 11
PM to 5
AM and had a peak during
the morning hours after awakening between 7
AM and 11
AM and another less
prominent peak during the evening between 7
PM and 10
PM. This circadian
variation in ischemic episodes was not statistically
significant
(P=0.3).
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The heart rate (± SD) during ST depression was
significantly higher than the mean heart rate during 48 hours (92±22
versus 70±8 bpm, P<0.001,
respectively). Mean heart rate at the onset of an ischemic
episode was 92±22 bpm; mean heart rate at the peak of an
ischemic episode was 106±18 bpm. A total of 17% of all
episodes was accompanied by a reduction of heart rate, 25% of all
episodes were accompanied by a small (1% to 15%) increase in heart
rate, and 42% of all episodes were accompanied by a significant
increase in heart rate (>15%). Three patients, with a total of 6
events (16%), had a heart rate at the onset of an ischemic
event 
130 bpm. No patient showed paroxysmal atrial
fibrillation.
ST-Segment Depression and Vascular
End-Organ Damage
Table 2 shows a comparison of
cardiovascular end-organ damage in patients with or
without ST-segment depression. Hypertensive patients with ST-segment
depression showed an increased IMT, expressed as total mean far-wall
IMT, and an increased frequency of plaques in the arterial
segments studied. Within the group of hypertensives with ST-segment
depression, the ischemic burden was not correlated with total
IMT (r=0.20,
P=0.38), nor with the mean
far-wall IMT of carotid
(r=0.16,
P=0.50) or femoral
(r=0.16,
P=0.08) artery segments,
respectively. Moreover, the ischemic burden was also not
associated with the total amount of plaques
(r=0.22,
P=0.33).
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ST-Segment Depression and Cardiac End-Organ
Damage
No significant difference was found in left
ventricular dimensions and left ventricular
mass index between the two groups. Rate-pressure product and the
systolic wall stress were not different between the two groups.
However, within the group of hypertensives with ST-segment depression,
left ventricular mass was significantly correlated with the
ischemic burden
(r=0.51,
P=0.02), as seen in
Figure 2, and with the duration of ST-segment depression
(r=0.51,
P=0.02). In left
ventricular geometry, the prevalence of hypertensives with
ST-segment depression was not significantly different over the four
groups. In the normal geometry group (n=49), 6 patients demonstrated
ST-segment depression. In the concentric remodeling group (n=105), 11
patients demonstrated ST-segment depression. Finally, in the eccentric
LVH group (n=12) and the concentric LVH group (n=12), only 2 patients
demonstrated ST-segment depression in each group.
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Factors Contributing to Ischemic
Episodes
From a variety of baseline characteristics, logistic
regression analysis identified pulse pressure
(P<0.05), body mass index
(P<0.05), and combined mean
far-wall IMT (P<0.05) as
significant independent factors relating to the occurrence of
ST-segment depression in these older hypertensive patients, as seen in
Table 3.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study documents a lower-than-expected prevalence of ST-segment depression in older hypertensive patients: 9% in women and 13% in men. Among the studies concerning hypertensive patients free from clinical signs of coronary artery disease but after antihypertensive drug treatment, the prevalence was reported to vary in the range of 23% to 37%.3 11 12 13 In the study of Zehender et al,3 hypertensive patients were selected on the basis of ineffective or untolerated antihypertensive treatment, whereas 2 other studies at variance with ours included obese patients (type I diabetics).11 12 Trenkwalder et al13 found 37% prevalence of ST-segment depression in an even older but smaller (n=41) hypertensive group with a mean age of 79 years (range, 70 to 94 years). Our findings comply with the Cardioscreening Study, which documented a prevalence of 15% of ST-segment depression during 48 hours of Holter monitoring or exercise stress testing in 414 mild to moderate hypertensives, but this was found in a younger age group (50 to 70 years of age). The majority of ST-segment depression was observed during Holter monitoring (10.9%) and a minority during exercise stress testing (6.1%), but in contrast with our results, ST-segment depression was more common for women than for men (17.5% versus 5.2%, respectively), and only 31% of their patients were previously untreated.14 It should be remarked that all our patients were in a primary care setting and were previously untreated for hypertension. In the unselected, population-based Cardiovascular Health Study, the prevalence of ST-segment depression in ambulatory ECGs in a sample of 1511 men and women >65 years of age was also similar to ours, with 9% in women and 13% in men.15 However, this study also included patients with conditions known to interfere with the ST segment, such as previous myocardial infarction, angina pectoris, atrial fibrillation, and digitalis medication. The majority of their participants was not hypertensive, and ambulatory monitoring was done for 24 hours instead of 48 hours, which has been shown to increase episodes of patients with asymptomatic ST-segment depression by
30%.16
Significance of ST-Segment Depression
The observed ST-segment depression in our study was
likely to reflect myocardial ischemia. Patients with specific
ECG abnormalities at rest that could have influenced the ST segment had
been excluded. Because left ventricular mass was not
significantly different in the groups with or without ST-segment
depression, repolarization abnormalities secondary to increased left
ventricular mass are not likely to be responsible for the
transient asymptomatic ST-segment depressions observed in
our population. Moreover, only two of these mild-to-moderate
hypertensive patients with ST-segment depression had concentric LVH,
and the rest of the patients with ST-segment depression were not
significantly different divided over the remaining left
ventricular geometry groups. The finding of a high
percentage of hypertensives with concentric remodeling and a relatively
low percentage of hypertensives with LVH is similar to a previous study
in primary care.17 Although
caution should be used in the interpretation of episodes of transient
ST-segment depression for patients free from clinical signs of
coronary artery disease, the absence of ST-segment depression
on resting ECG, the circadian pattern, and the relation with heart rate
of the majority of the events observed are compatible with being
episodes of silent myocardial ischemia.
Mechanisms of Myocardial
Ischemia
This study shows that vascular remodeling induced by
hypertension is an important determinant for silent ischemia.
Therefore, the threshold for ischemia to develop depends mainly
on vascular supply factors in older hypertensives, whereas cardiac
demand factors mainly determine the extent of the ischemia.
Both structural factors such as intima-media hypertrophy
and arterial plaques and functional factors such as
increased vasomotor tone caused by abnormal
endothelium-derived relaxation play a crucial role in
the induction of transient myocardial
ischemia.18 19
Although increased IMT as assessed by B-mode ultrasound imaging is only
moderately correlated to the percentage of coronary
stenosis as assessed by quantitative coronary
arteriography,20 there is
some evidence that increased IMT in older subjects is associated with
asymptomatic ischemia, as evidenced by exercise ECG
or exercise thallium
scintigraphy.21
The observed difference in pulse pressure, positively related with
increased IMT,22 partly
supports the view of the vascular supply being the major determinant
for the occurrence of ischemic ST-segment depression because
pulse pressure can also be expressed as a determinant of myocardial
oxygen demand.
Myocardial demand appears to be less important for the occurrence of ischemic ST-segment depression because left ventricular mass and LVH do not explain the occurrence of transient ST-segment depression in these older hypertensives. These findings are in agreement with those of previous studies that did not reveal any difference between left ventricular mass of hypertensives with and those without ischemia.1 12 13 14 23 Moreover, the lower body mass index in the group with ST-segment depression further suggests that the occurrence of ischemic ST-segment depression is not primarily determined by cardiac demand because overweight has been reported to be associated with increased left ventricular mass.24 A possible explanation might be the reduced level of physical activity among overweight subjects. Our findings are supported by findings from the Cardiovascular Health Study, in which overweight was associated with a 33% reduction of likelihood of ischemic episodes after adjustment for other risk factors.15
The severity of myocardial ischemia, expressed as ischemic burden, is mainly determined by cardiac demand factors because increased myocardial mass rather than vascular abnormalities was associated with the extent of transient ST-segment depression. This might be associated with endothelial dysfunction because recently a significant relation was found between increased left ventricular mass and endothelial dysfunction in hypertensive patients.25 In contrary, the ischemic burden was not associated with structural vascular supply factors such as IMT and arterial plaques.
Conclusions
Our study provides strong evidence that in older
hypertensives, the occurrence of ischemic ST-segment depression
is determined mainly by vascular factors rather than left
ventricular mass. Thus, supply markers such as IMT and
arterial plaques as markers of generalized
atherosclerosis are mainly responsible for the
occurrence of ischemic ST-segment depression, and demand
markers such as left ventricular mass are mainly
responsible for the ischemic burden. The occurrence of silent
ischemia during daily life has been found to be an independent
predictor of cardiovascular events in hypertensive
patients.4 26
Until now, the risks of myocardial infarction and
cardiovascular death associated with the occurrence of
silent ischemia in hypertensive patients are unknown. However,
the early detection of silent myocardial ischemia by Holter
monitoring might be useful for the identification of hypertensive
patients who should be investigated further and considered for a more
specific treatment.
Received March 16, 2000; first decision April 11, 2000; accepted October 2, 2000.
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