(Hypertension. 1997;30:1382-1388.)
© 1997 American Heart Association, Inc.
Articles |
Relation of Exercise-Induced Myocardial Ischemia to Cardiac and Carotid Structure
From the Division of Cardiology, Department of Medicine, The New York Hospital- Cornell Medical Center, New York, NY.
Correspondence to Peter M. Okin, MD, The New York Hospital–Cornell Medical Center, 525 E 68th St, New York, NY 10021. E-mail pokin{at}mail.med.cornell.edu
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Abstract |
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Abstract There is a strong relation of carotid atherosclerosis to coronary artery disease and left ventricular hypertrophy. In addition, abnormalities of carotid structure are strongly associated with abnormal left ventricular geometry and structure. However, little is known regarding the relation of exercise-induced ST depression to carotid atherosclerosis, carotid, or left ventricular structure in the absence of apparent coronary disease. The relationship of exercise ECG myocardial ischemia to the presence of carotid atherosclerosis and to carotid and left ventricular structure was assessed in 204 asymptomatic subjects free of clinical evidence of cardiovascular disease. Myocardial ischemia on the exercise ECG, defined by a chronotropically adjusted ST/HR slope of >3.47 µV/bpm, was associated with a nearly threefold greater likelihood of discrete carotid atherosclerosis (50% [6 of 12] versus 17% [29 of 192], P=.007) and with older age, male sex, higher systolic and diastolic blood pressures, greater left ventricular mass and mass index, and greater common carotid artery intimal-medial thickness and cross-sectional area index. Stepwise logistic regression analyses, including standard risk factors, revealed that only carotid artery cross-sectional area index (P=.0007) and systolic blood pressure (P=.005) independently predicted an abnormal chronotropically adjusted ST/heart rate slope. Moreover, among 132 subjects with
10 µV of ST-segment depression,
only left ventricular mass index and carotid artery
cross-sectional area index were significant predictors of the
chronotropically adjusted ST/heart rate slope response. Subendocardial
ischemia on the exercise ECG is strongly associated with the
presence of carotid atherosclerosis and is related to
systolic blood pressure, carotid artery cross-sectional area
index, and left ventricular mass index, independent of age,
sex, and other cardiac risk factors. These findings provide additional
insights into the relation between coronary and carotid
atherosclerosis and suggest that an association among
ischemia and left ventricular and carotid
structural abnormalities may contribute to the pathogenesis of
coronary events.
Key Words: atherosclerosis • carotid arteries • electrocardiography • exercise • heart rate • hypertrophy • ischemia
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Introduction |
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The association between carotid atherosclerosis and coronary artery disease is well established.1 2 3 4 5 6 7 Previous studies have shown that a high proportion of patients with carotid stenosis have evidence of coronary artery disease1 2 3 4 5 6 and that coronary disease is a major cause of morbidity and mortality in patients with cerebrovascular disease.3 4 7 Indeed, exercise-induced myocardial ischemia as manifested by ECG ST-segment depression5 6 or abnormal thallium myocardial perfusion imaging6 is frequently found in patients with cerebrovascular disease and no history of coronary disease. However, little is known regarding the relation of ST-segment measures of exercise-induced ischemia to carotid structure or the prevalence of discrete carotid atherosclerosis in asymptomatic patients.
Additional observations have documented a relation between both echocardiographic and ECG LVH and the presence of carotid atherosclerosis8 9 and further suggest that geometric and functional changes in the common carotid artery parallel changes in LV structure and function.10 11 12 13 In addition, the predictive value of echocardiographic LVH for subsequent cardiovascular morbidity and mortality14 15 16 17 18 19 20 provides strong evidence for relations between LVH and ischemic heart disease as well as cerebrovascular disease. Moreover, hypertension and LVH have both been associated with exercise-induced evidence of myocardial ischemia in the absence of obstructive coronary artery disease,21 22 23 24 25 26 possibly reflecting an underlying impairment of coronary vascular reserve.23 27 28 29 However, the relation of ST-segment measures of exercise-induced ischemia to LV dimensions and mass have not been carefully examined. Therefore, the purposes of the present study were to assess the relationship of exercise ECG evidence of inducible myocardial ischemia to carotid atherosclerosis and to carotid and LV structure.
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Methods |
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Study Population
The study included 163 normotensive subjects and 41 untreated hypertensive subjects who underwent treadmill exercise, resting ECG, transthoracic echocardiography, and carotid ultrasonography as part of several ongoing, longitudinal studies.8 9 All 204 subjects were asymptomatic, were free of clinical evidence of coronary artery or cerebrovascular disease, and were without Q-wave myocardial infarction, resting ST-segment abnormalities, or left or right bundle-branch block on their 12-lead ECG. The presence of valvular heart disease was excluded by Doppler echocardiography. The study was performed in accordance with protocols approved by the Committee on Human Rights in Research of Cornell University Medical College.
Exercise ECG
Exercise ECGs were performed on a treadmill according to the
Cornell protocol30 with a computerized exercise system
modified by the addition of a bipolar lead CM5, as
previously described in detail.31 32 33 ST-segment amplitudes
were measured by computer to the nearest 10 µV at a point 60 msec
after the J point.30 31 32 Exercise tests were evaluated by a
single investigator (P.M.O.) who was blinded to the results of both
echocardiography and carotid ultrasonography using
standard ECG criteria based on the measured amount of ST-segment
depression on the peak exercise ECG and were considered positive in the
presence of 100 µV of additional horizontal or downsloping ST
depression.31 32 33
Calculation of the maximal ST/HR slope was performed using linear regression analysis to relate the magnitude of ST-segment depression in each lead (except aVR, aVL, and V1, which were excluded from all analyses) to heart rate at the end of each stage of exercise and at peak exercise, according to methods previously reported in detail.31 32 33 The highest ST/HR slope with a significant coefficient of correlation among all the leads was taken as the test result. Based on previous work demonstrating that correction of the ST/HR slope for an attenuated heart rate response to exercise improves performance of the ST/HR slope,33 the chronotropically adjusted ST/HR slope was obtained by dividing the slope value by the fraction of HRR achieved at peak exercise. Fraction HRR achieved was calculated as fraction HRR=(HRpeak-HRrest/(100% MPHR-HRrest), where HRpeak is the heart rate at peak exercise, HRrest is the heart rate on the standing preexercise ECG, and 100% MPHR is the age-predicted target heart rate.33 The resultant chronotropically adjusted ST/HR slope was considered abnormal when >3.47 µV/bpm, a partition previously demonstrated to have a specificity of 96% in a separate population of normal subjects.33
Echocardiography
All subjects underwent standard M-mode and two-dimensional
echocardiography using echocardiographs
equipped with 2.5- and 3.5-MHz imaging transducers. LV dimensions were
obtained from two-dimensionally guided M-mode tracings or, if M-mode
tracings were technically inadequate, from the two-dimensional study,
according to the recommendations of the American Society of
Echocardiography.34 35 LV mass was
calculated according to an anatomically validated
formula,36 and LVH was considered present if LV mass
index was >110 g/m2 in women or >125 g/m2 in
men.14 16 37
Carotid Ultrasound
Imaging of both carotid arteries was performed in all subjects
using 7.0- or 7.5-MHz imaging transducers as previously
described.8 11 Carotid atherosclerosis was
defined as the presence of discrete plaque 50% greater than the
surrounding wall within any segment of either carotid
artery.38 Two-dimensionally guided M-mode tracings of the
distal common carotid artery 
1 cm proximal to the bulb were
recorded on videotape and subsequently digitized with a frame
grabber. Intimal-medial thickness of the far wall and internal diameter
of the artery at end diastole were measured with electronic
calipers on several cycles and averaged. These measurements were never
obtained at the level of discrete carotid plaque.
Data Analysis and Statistical Methods
Data are presented as the mean±SD according to exercise
test response. Continuous variables were compared using Student's
t test or one-way ANOVA followed by the Scheffé
posthoc test for multiple comparisons and were further compared between
groups after adjustment for age and gender or for age, gender, and
height using ANCOVA. Differences in prevalences between groups were
compared using 
2 analysis or Fisher's exact
test when appropriate. The relation between chronotropically adjusted
ST/HR slope response and clinical, echocardiographic,
and carotid variables was assessed by stepwise multiple linear
regression. The independent predictive power of risk factors and LV and
carotid variables for an abnormal exercise test defined by
chronotropically adjusted ST/HR slope was determined using forward
stepwise logistic regression analysis. For all tests, a value
of P<.05 was required for rejection of the null
hypothesis.
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Results |
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Standard test criteria were positive in 4% (9 of 204) of subjects, and chronotropically adjusted ST/HR slope criteria were positive in 6% (12 of 204) of subjects (P=NS). There was a low degree of agreement between methods for test positivity: both tests were positive in 4 subjects, 5 subjects had a positive test by standard criteria only, and 8 subjects had abnormal chronotropically adjusted ST/HR slopes but negative standard tests. Clinical and demographic characteristics of subjects are examined according to exercise test result in Table 1
. Subjects with a
positive test by standard ECG criteria were significantly more likely
to be male, had higher systolic and diastolic blood
pressures, had marginally lower HDL cholesterol levels, had
trends toward a greater prevalence of clinical hypertension and
cigarette smoking, and had slightly higher body surface areas, which
likely reflects the male preponderance. Subjects with positive tests by
chronotropically adjusted ST/HR slope criteria were older, more
commonly male, had a higher prevalence of clinical hypertension, had
higher systolic and diastolic blood pressures, were
most often current or former smokers, and had higher total
cholesterol levels and higher body surface areas.
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Echocardiographic measures of LV structure and
function are examined according to exercise test response in Table 2. Subjects with positive standard test
responses had greater LV end-diastolic diameters but
similar septal and posterior wall thicknesses compared with subjects
with negative standard test responses and, as a consequence, had
slightly greater indexed and unindexed LV mass. An abnormal test by
chronotropically adjusted ST/HR slope criteria was associated with
larger LV end-diastolic dimensions, greater wall
thicknesses, and significantly greater LV mass and mass index; the
differences in mass and mass index persisted after adjustment for
baseline differences in gender and age.
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Ultrasound measures of carotid artery structure and the presence of
discrete carotid plaque were examined according to exercise test
response in Table 3. According to
standard test criteria, subjects with positive exercise tests had
similar end-diastolic diameter but greater intimal-medial
wall thickness and relative wall thickness and greater carotid
cross-sectional area than subjects with negative tests. However, there
was no difference in the prevalence of carotid plaque in subjects with
positive and negative standard test responses (11% versus 17%,
P=NS). Positive tests by chronotropically adjusted ST/HR
slope criteria identified a small group of subjects with much greater
carotid end-diastolic dimension, wall thickness, relative
wall thickness, and cross-sectional area than those with negative
tests. The differences in carotid end-diastolic diameter
and intimal-medial wall thickness persisted after adjustment for group
differences in age and gender, and the difference in cross-sectional
area measurements remained significant after adjustment for age,
gender, and height. Moreover, in contrast to standard test criteria, a
positive chronotropically adjusted ST/HR slope identified a group of
subjects with a nearly threefold higher prevalence of discrete carotid
plaque (50% versus 17%, P=.007).
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To determine whether there was a relationship of LV and carotid
structure to chronotropically adjusted ST/HR slope response below the
threshold diagnostic partition that was developed to detect
coronary disease, subjects were arranged into three groups with
adjusted ST/HR slope values of 0 (group 1, n=89), between 0 and the
threshold partition of 3.47 (group 2, n=103), and >3.47 (group 3,
n=12); age and gender were similar in groups 1 and 2. Subthreshold
levels of chronotropically adjusted ST-segment depression were not
associated with greater LV or carotid dimensions: compared with
subjects with no ST-segment depression (group 1), subjects in group 2
with chronotropically adjusted ST/HR slope values of 
3.47 had nearly
identical mean LV and carotid dimensions, similar LV mass and mass
index (Table 4), and a similar prevalence
of discrete carotid plaque (Fig 1). In
contrast, an abnormal chronotropically adjusted ST/HR slope remained
associated with greater LV and carotid dimensions, greater LV mass, and
a significantly higher prevalence of carotid plaque compared with both
group 1 and group 2 subjects (Table 4 and Fig 1).
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The relationship of the chronotropically adjusted ST/HR slope response
to exercise to demographic, clinical, LV, and carotid variables was
further examined using multivariable linear regression (Table 5) and logistic regression
analyses (Table 6). When all 204
subjects were evaluated, linear regression analysis revealed
that only clinic systolic blood pressure (partial
r=.33) and carotid cross-sectional area index (partial
r=.18), a measure that takes into account both internal
diameter and intimal-medial thickness,12 remained
significant linear correlates of the chronotropically adjusted ST/HR
slope. However, when the 72 subjects with no ST-segment depression at
end exercise were excluded from analysis, only LV mass index
(partial r=.38) and the carotid artery cross-sectional area
index (partial r=.23) correlated independently with the
chronotropically adjusted ST/HR slope. Stepwise logistic regression
analysis in the entire population (Table 6), including standard
risk factors, age, sex, blood pressure determinations, and both
echocardiographic and ultrasound measurements, revealed
that both carotid artery cross-sectional area index and
systolic blood pressure were significant predictors of an
abnormal chronotropically adjusted ST/HR slope response. When only the
132 subjects with ST-segment depression at end exercise were included
in the logistic regression analysis, only carotid
cross-sectional area index and LV mass index were significant
predictors of an abnormal chronotropically adjusted ST/HR slope
response. Importantly, if the same variables were forced into the
logistic regression analyses, carotid cross-sectional area
index remained a significant predictor of an abnormal adjusted ST/HR
slope response in the overall population (P=.006) and was a
significant predictor in the 132 subjects with ST-segment depression
(P=.01), as was LV mass index (P=.04).
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Discussion |
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This study demonstrates a significant relationship between exercise-induced myocardial ischemia, as reflected by an abnormal chronotropically adjusted ST/HR slope, and increases in carotid cross-sectional area index, systolic blood pressure, and LV mass index. These associations of exercise-induced ischemia with carotid hypertrophy, blood pressure, and LV mass are independent of the presence of frank echocardiographic LVH or discrete carotid plaque, are independent of other traditional cardiac risk factors, and occur in asymptomatic subjects with no clinical or rest ECG evidence of previous myocardial infarction. These findings provide new insights into the relation between coronary and carotid atherosclerosis and suggest that associations of inducible ischemia to LV and carotid structural abnormalities may contribute to the pathogenesis of coronary events in patients with carotid atherosclerosis.
Relation of Carotid Structure and Atherosclerosis
to Exercise-Induced Ischemia
In a study of 778 asymptomatic,
hyperlipidemic patients who had exercise ECGs and
carotid ultrasonography,5 the presence of isolated carotid
intimal thickening of >1 mm was associated with a trend toward an
increased prevalence of a positive ECG by standard criteria (7.8%
versus 3.8%, P=.11), but differences in carotid dimensions
according to exercise test response were not examined. In the
present study, a positive exercise ECG by both standard and heart
rate–adjusted criteria were associated with increases in mean carotid
artery wall thickness, relative wall thickness, and carotid artery
cross-sectional area. However, an abnormal chronotropically adjusted
ST/HR slope identified subjects with greater increases in carotid
dimensions. These findings, taken together with the higher sensitivity
of the chronotropically adjusted ST/HR slope than of standard exercise
ECG criteria for the detection of coronary
disease,33 further support previous observations of an
association between carotid hypertrophy and
coronary heart disease.39 40
The correlation between carotid atherosclerosis and coronary artery disease has been more clearly established,1 2 3 4 5 6 7 but only one previous study has directly examined the relationship of discrete carotid plaque to exercise ECG findings.5 In the same study of 778 patients, Bruckert et al5 found a significant association between a positive ECG test and the degree of carotid atherosclerosis when carotid arteries were characterized as normal or having intimal thickening, discrete nonobstructive plaque, or significant stenosis. However, similar to the present study, there was no significant difference in the prevalence of discrete plaque between subjects with positive and negative tests (24% versus 23%, P=NS). In contrast, a positive exercise ECG by chronotropically adjusted ST/HR slope criteria was associated in the present study with a nearly threefold increased prevalence of carotid plaque. A previous study from our laboratory9 demonstrated that rest ECG evidence of ischemia was also associated with a threefold higher prevalence of discrete carotid plaque in asymptomatic normotensive or hypertensive adults, further solidifying the association between ECG measures of ischemia and carotid atherosclerosis.
LV Structure and Exercise-Induced Ischemia
Both hypertension and LVH have been associated with
exercise-induced evidence of myocardial ischemia, even in the
absence of obstructive coronary disease.21 22 23 24 25 26
However, the relationship between ST-segment changes during exercise
and LV dimensions and mass has not been well characterized. In a small
study of 20 patients >50 years old with atypical chest pain, normal
exercise thallium studies, no history of coronary disease, and
no ECG evidence of LVH,24 the 10 patients with a positive
test by standard criteria had significantly greater mean posterior wall
thickness (10.6±1.8 versus 8.9±0.9 mm) and greater mean LV mass
index (119±32 versus 89±15 g/m2) than the 10 patients
with negative exercise ECGs. However, a negative test was defined as
having 0.5 mm of ST-segment depression at an exercise heart rate
of 85% of age-predicted maximum, thus excluding patients with
intermediate test results that would normally be considered negative
studies and potentially biasing the results. In the present study,
although a positive test by standard test criteria identified a small
group of subjects with slightly greater LV internal dimensions and
slightly higher LV mass, an abnormal chronotropically adjusted ST/HR
slope identified a slightly larger group of subjects with significantly
greater LV dimensions, wall thicknesses, and both indexed and unindexed
mass. Indeed, among subjects who demonstrated any degree of ST-segment
depression at peak exercise, LV mass index remained an independent
correlate of the degree of chronotropically adjusted ST/HR slope
response and an independent predictor of an abnormal test response by
these criteria.
The etiology of ST-segment changes in our patients remains uncertain. These findings could represent the presence of clinically silent coronary disease and/or reflect the decreased coronary vasodilator reserve that has been observed in patients with hypertension28 and in patients with hypertension and increased LV wall thickness27 28 in the absence of coronary disease. Thus, the lower test specificity of ST-segment depression criteria for the presence of coronary disease in patients with hypertension and LVH21 22 26 may at times reflect a true association with ischemia in the absence of obstructive coronary disease.
Standard and Heart Rate–Adjusted ST-Segment Depression
Criteria
These findings, and the significantly higher sensitivity of the
chronotropically adjusted ST/HR slope for the identification of
coronary disease,33 further support the argument
that heart-rate–adjusted ST-segment depression criteria, and in
particular the chronotropically adjusted ST/HR slope, more accurately
reflect the presence and severity of myocardial
ischemia.31 32 33 Although both standard and
chronotropically adjusted ST/HR slope criteria separated subjects
according to LV and carotid artery structure, an abnormal
chronotropically adjusted ST/HR slope identified subjects with
apparently greater cardiac and vascular structural abnormalities, and
only an abnormal chronotropically adjusted slope identified a small
group of subjects with a significantly higher likelihood of discrete
carotid plaque. These findings parallel the greater sensitivity of the
chronotropically adjusted ST/HR slope for detection of coronary
disease compared with standard ST-segment depression
criteria.33 The similar prevalence of carotid plaque and
nearly identical mean values for LV and carotid structural
variables found in groups 1 and 2 further suggest that values of
chronotropically adjusted ST/HR slope below the threshold partition of
3.47 µV/bpm are not associated with significant carotid or LV
structural abnormalities.
Summary
The present study documents a high prevalence of carotid
atherosclerosis in asymptomatic subjects
with no clinical evidence of either coronary or cerebrovascular
disease who have evidence of exercise-induced ischemia as
manifested by an abnormal chronotropically adjusted ST/HR slope.
Moreover, we found that carotid cross-sectional area indexed for body
size, a variable that by incorporating both increases in luminal
diameter and intimal medial thickness12 may more accurately
reflect generalized atherosclerosis in the carotid
artery,41 was an independent predictor of ischemia
during exercise. These findings have important prognostic implications.
In addition to the well known relationship of obstructive carotid
disease and asymptomatic carotid plaque to adverse cardiac
events,3 4 7 42 increased carotid intimal-medial thickness
alone has been linked to an increased risk of cardiac morbidity in a
variety of epidemiologic studies.3 7 Together with the
increased cardiac morbidity and mortality associated with abnormal
heart rate–adjusted ST-segment depression indexes,43 44
these findings suggest that asymptomatic individuals with
carotid thickening due to atherosclerosis or
hypertrophy and exercise-induced ischemia may be at
a substantially increased risk of future coronary events. The
association of an abnormal chronotropically adjusted ST/HR slope with
LV mass index raises the question of whether correcting ST-segment
depression for an accurate ECG measure of LV mass might improve
accuracy of the exercise ECG for the detection of coronary
disease.45 Further study will be necessary to clarify these
issues.
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Selected Abbreviations and Acronyms |
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Received May 28, 1997; first decision June 30, 1997; accepted July 9, 1997.
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