(Hypertension. 2000;35:580.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Continuous Relation Between Left Ventricular Mass and Cardiovascular Risk in Essential Hypertension
From the Divisione di Medicina (G.S.), Ospedale "Beato G. Villa," Città della Pieve, Italy; Dipartimento di Scienze Cardiologiche (P.V., C.P.), Ospedale "R. Silvestrini," Perugia, Italy; and Dipartimento di Medicina Sperimentale e Clinica (O.C., C.C., F.P.), Università degli Studi di Catanzaro, Italy.
Correspondence to Dr Giuseppe Schillaci, Ospedale "Beato G. Villa," Divisione di Medicina, via Beato G. Villa, 1-06062 Città della Pieve PG, Italy. E-mail skill{at}ftbcc.it
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Abstract |
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Abstract—The detection of left ventricular (LV) hypertrophy on echocardiography is a powerful risk indicator in essential hypertension. However, the prognostic impact of LV mass values within the "normal" range and the shape of the relation between LV mass and prognosis remain unclear. Thus, 1925 white subjects with uncomplicated essential hypertension underwent off-therapy 24-hour blood pressure monitoring and M-mode echocardiography. During 4.0±2 years of follow-up, there were 181 major cardiovascular events (2.4/100 patient-years) and 49 deaths from all causes. In the 5 gender-specific quintiles of LV mass distribution (partition values: 92, 105, 120, and 138 g/m2 in men and 79, 91, 102, and 116 g/m2 in women), cardiovascular event rates were 0.8, 1.7, 2.2, 2.9, and 4.3 per 100 patient-years. After adjustment for several risk factors, including 24-hour ambulatory blood pressure, the relative risk (RR) of developing a cardiovascular event increased progressively from the first quintile (RR 1) to the second (RR 1.6, 95% CI 0.8 to 3.1), third (RR 1.9, 95% CI 1.01 to 4.0), fourth (RR 3.0, 95% CI 1.5 to 5.8), and fifth (RR 3.5, 95% CI 1.8 to 6.8) quintile. For all-cause death, the RR in the fifth quintile compared with the first quintile was 4.3 (95% CI 1.2 to 13.4). In conclusion, the powerful relation between LV mass and risk of cardiovascular disease in subjects with uncomplicated essential hypertension is continuous over a wide range of LV mass values, even below the current "upper normal" limits. The relation remains significant after control for traditional risk factors, including ambulatory blood pressure.
Key Words: echocardiography • hypertension, arterial • hypertension, essential • hypertrophy • morbidity • mortality
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Introduction |
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Left ventricular (LV) hypertrophy detected on echocardiography is a powerful and independent predictor of cardiovascular complications and death in subjects with uncomplicated essential hypertension.1 2 3 Furthermore, regression of LV hypertrophy appears to be a favorable prognostic marker independent of the treatment-induced reduction in blood pressure (BP).4 5
LV mass shows a continuous distribution in the general population,6 whereas LV hypertrophy is an operational category that defines the upper end of LV mass distribution.1 2 3 LV hypertrophy on echocardiography is generally found in 20% to 30% of relatively unselected subjects with mild-to-moderate hypertension,7 8 and its prevalence varies according to the selected cutoff value.9 The Framingham Heart Study showed an apparently continuous relation between LV mass and cardiovascular event rate in the general population.10 However, the important clinical issues regarding the shape of the relation between LV mass and cardiovascular risk in essential hypertension and the prognostic impact of LV mass values below the commonly agreed-on upper normal limits have not been addressed. The present study was specifically designed to establish the link between LV mass and cardiovascular risk in subjects with essential hypertension over a wide range of LV mass distribution. The study was a collaborative project between 2 observational registries of subjects with essential hypertension.
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Methods |
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Study Populations
The Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study is a prospective registry of complications and death in white adult subjects with essential hypertension. The study design and procedures have been reported previously.3 5 Hypertensive subjects were referred to 1 of 3 participating centers (Perugia, Città della Pieve, and Castiglione del Lago) for baseline evaluation by a group of general practitioners practicing in Umbria, in central Italy. A total of 1686 subjects enrolled between 1988 and 1996, for whom good-quality echocardiographic recordings and complete follow-up data are available, were included in the present analysis.
A parallel cohort study was performed in a group of white adult hypertensive subjects at the University Hospital of Catanzaro, Catanzaro, Italy. A total of 239 subjects with good-quality echocardiographic recordings and complete follow-up data, who were enrolled between 1990 and 1997, are included in the present analysis. Selected clinical characteristics of the 2 populations are reported in Table 1.
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Inclusion Criteria
All study subjects fulfilled the following criteria: (1) clinic
systolic BP of 
140 mm Hg, diastolic BP of
90 mm Hg, or both on 3 visits at 1-week intervals; (2) no
previous treatment for hypertension (70%) or withdrawal from
antihypertensive drugs 4 weeks before the study; (3) no clinical or
laboratory evidence of heart failure, coronary heart disease,
previous stroke, valvular defects or secondary causes of
hypertension, or important concomitant disease; (4) good-quality
echocardiographic recordings (see later); and
(5) 1 valid BP measurement per hour over the 24 hours. All subjects
gave informed consent to participate in the study.
BP Measurement
Clinic BP was measured by a physician in the hospital clinic
with a mercury sphygmomanometer, after the subject sat for 10
minutes. The average of 3 measurements on 2 sessions was considered
for the analysis. Ambulatory BP was recorded with an
oscillometric device (models 90202 and 90207; SpaceLabs) that was set
to take a reading every 15 minutes throughout the 24 hours. Normal
daily activities were allowed and encouraged, and patients were told to
keep their nondominant arm still and relaxed to the side during
measurements. Reading, editing, and analysis of data were
performed as previously described.11
Echocardiography
The M-mode echocardiographic study of the left
ventricle was performed under 2-dimensional control. Measurements were
taken according to the American Society of
Echocardiography recommendations.12
Only frames with optimal visualization of interfaces that
simultaneously show the septum, LV internal diameter, and
posterior wall were used for readings. Tracings were read by 2
observers in the PIUMA cohort and by 2 observers in the Catanzaro
cohort, and the mean value from 5 measurements per observer was
computed. All readers were unaware of patients’ clinical data. The
intraobserver and inter-observer variabilities in the PIUMA study
laboratory have been reported elsewhere.6 Intraobserver
coefficients of variation in the Catanzaro study laboratory were 4.6%
for interventricular septum, 4.6% for posterior wall,
1.5% for internal diameter, and 6.3% for LV mass. LV mass was
calculated according to Devereux et al13 and normalized by
both body surface area and
height2.7,14 to correct for the
effect of overweight.
Follow-Up Procedures and End Point Evaluation
All subjects were followed by their family physicians in
cooperation with the outpatient clinic of the referring hospital and
treated with the aim of reducing clinic BP to <140/90 mm Hg
through the use of standard lifestyle and pharmacological measures.
Most patients continue to be periodically referred to our institutions
for BP control and other diagnostic procedures.
Diuretics, ß-blockers, ACE inhibitors,
Ca2+ channel blockers, and
1-blockers, alone or in various combinations,
are the antihypertensive drugs that are most frequently
prescribed. Contacts with family physicians and telephone interviews
were periodically undertaken to determine the incidence of major
cardiovascular complications of hypertension. For the
subjects who developed a cardiovascular morbid event,
hospital record forms and other available original source documents
were reviewed in conference by the authors.
Cardiovascular events included new-onset
coronary artery disease (myocardial infarction, unstable angina
with documentation of ischemic electrocardiographic changes,
sudden cardiac death, or coronary
revascularization procedure), stroke, transient
cerebral ischemic attack, symptomatic aortoiliac
occlusive disease verified with angiography, thrombotic occlusion of a
retinal artery documented with fluoroangiography, progressive heart
failure that required hospitalization, and renal failure that required
dialysis. Transient ischemic attack was defined by the
diagnosis by a physician of any sudden focal neurological deficit that
cleared completely in <24 hours. Heart failure was defined by the
presence of 2 major criteria or 1 major plus 2 minor criteria as
reported in the Framingham Heart Study.15 The
international standard criteria used to diagnose
cardiovascular events in the PIUMA study have been
described elsewhere.3 5 16
Statistical Analysis
Because the 2 cohorts differed in some clinical characteristics
(Table 1), analyses have been adjusted for the "center
effect" as reported by de Simone et al.17 Briefly, BP
and primary echocardiographic measurements (LV internal
dimension and wall thickness) were related as dependent variables
to a dummy variable indicating the center (0 or 1). The
variables considered in this analysis were therefore
adjusted with the linear coefficient of regression (b).
Thus, the adjusted variable (adjV) was
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is the dummy variable representing the center, and µ
is the average value of the variable representing the
center.
Parametric data are reported as mean±SD. Standard descriptive
and comparative analyses were undertaken. The rates of events
are presented as the number of events per 100 patient-years
based on the ratio of the number of events observed to the total number
of patient-years of exposure up to the terminating event or censor. For
the patients without events, the date of censor was that of the last
contact with the patient. For the subjects who experienced multiple
events, survival analysis was restricted to the first event.
For subjects who subsequently died, classification of the terminating
event could differ from that of the previous nonfatal event. Survival
curves were estimated with the use of the Kaplan-Meier
product-limit method18 and compared with the use of
the Mantel (logistic-rank) test.19 The effect of
prognostic factors on survival was evaluated with use of the stepwise
Cox semiparametric regression model.20 The
assumption of linearity for the Cox model was tested through visual
inspection, and no violation of proportional hazards was found. We
tested the variables of age (years), gender (women, men), serum
cholesterol (in mmol/L), smoking habits (previous or
never smokers, current smokers), body mass index (body weight [in kg]
divided by the square of the height [in m]), clinic and 24-hour
systolic and diastolic BP (in mm Hg),
diabetes (no, yes), and antihypertensive drug treatment at the time of
follow-up contact (no, yes). LV mass was considered both as a
continuous variable and according to gender-specific quintiles of
LV mass adjusted for body surface area. The partition values between
quintiles were 92.3, 105.4, 119.8, and 138.2 g/m2
in men and 79.5, 91.2, 101.8, and 116.4 g/m2 in
women. We also tested the prognostic value of LV
hypertrophy defined as a binary variable, after
correction for body surface area (LV mass 125
g/m2 in both genders1 2 3 or LV mass
125 g/m2 in men and 110
g/m2 in women21 ) and for body height
(LV mass 51.0 g/m2.7 in both
genders14 ).
The extent to which the observed data were fitted by a particular model
was tested with the use of the -2 logistic likelihood (-2 log L)
statistics.22 This procedure compares alternative models
fitted to the same set of survival data, based on the consideration
that the likelihood function summarizes the information that the data
contain about unknown parameters in a given model. The
likelihood function is expressed by a number between 0 and 1, and the
inverse of its logarithm is commonly used for longitudinal statistics.
Differences between the odds ratios were assessed with the
2 distribution of the difference between two
-2 log Ls. A significant difference between the -2 log L statistics
provided through the use of different methods indicates a better
prediction of risk estimate yielded by the method leading to the lowest
-2 log L value. SPSS statistical package, release 7.5 (SPSS Inc), was
used to perform the analyses. P<0.05 was considered
statistically significant.
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Results |
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Clinical Characteristics
Table 2 reports the main clinical characteristics of the study population by quintiles of LV mass index. Compared with the first quintile, subjects with higher values of LV mass index were older and had a greater body mass index. In addition, BP values, both clinic and ambulatory, were higher than those for patients in the first quintile of LV mass. Serum cholesterol levels and prevalence of smokers and diabetic subjects did not differ between the groups. The prevalence of LV hypertrophy, defined as an LV mass of
125
g/m2 in both genders, was 24.1% (n=463). The
prevalence increased to 30.5% (n=587) when LV hypertrophy
was defined as an LV mass of 125 g/m2 in men
and 110 g/m2 in women and to 40.3% (n=775)
when LV mass was adjusted for body height (LV mass 51.0
g/m2.7 in both genders). By selection, subjects
in the upper quintiles of the distribution of LV mass had a greater
wall thickness, LV internal diameter, and LV mass than the subjects in
the first quintile. In addition, relative wall thickness progressively
increased with increasing LV mass.
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Outcome Events
During a mean follow-up period of 4.0±2 years (range 1.0 to 8.3
years), there were 181 new cardiovascular morbid events
(2.42 events/100 patient-years) at the cardiac (n=96), cerebrovascular
(n=64), or peripheral vascular (n=21) level. Specifically,
there were 31 subjects with myocardial infarction, 4 with sudden
cardiac death, 1 with cardiac death from other causes, 34 with unstable
angina, 12 with coronary revascularization
procedures, 14 with heart failure that required hospitalization, 46
with stroke, 18 with transient cerebral ischemia, 14 with
new-onset aortoiliac occlusive disease, 3 with occlusion of the retinal
artery verified with fluoroangiography, and 4 with renal failure that
required dialysis.
During follow-up, we also registered 49 deaths from all causes (0.63 event/100 patient-years), of which 26 were from cardiovascular causes (6 fatal myocardial infarctions, 6 sudden cardiac deaths, 4 other cardiovascular deaths, and 10 fatal strokes), 14 were from neoplastic causes, and 9 were from other causes.
Cardiovascular Morbidity Rates
As shown in Figure 1 (left), the
rate of total (fatal plus nonfatal) cardiovascular
events (per 100 patient-years) was 0.85, 1.66, 2.24, 2.86, and 4.34 in
the first, second, third, fourth, and fifth quintile of LV mass,
respectively, and this difference was highly significant (log-rank
test, P<0.0001). Event-free survival curves in the 5
quintiles of LV mass are shown in Figure 2. The cumulative
cardiovascular event rate for the highest quintile was
35% at 8 years compared with a cumulative rate of <10% for the
lowest quintile.
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A significant risk gradient for adverse events was evident across the quintiles of LV mass after adjustment for age, gender, smoking, diabetes, cholesterol level, clinic and 24-hour ambulatory BP, treatment status, body mass index, family history, and LV relative wall thickness. As reported in Table 3, LV mass was independently associated with a progressive, linear increase in cardiovascular morbidity rates. In a multivariate analysis, the excess risk compared with the first quintile of LV mass was significant for the third, fourth, and fifth quintiles (LV mass >91.2 g/m2 in women and >105.4 g/m2 in men). When LV mass was indexed to height2.7 in the place of body surface area, the risk gradient across quintiles did not change substantially for the second (relative risk [RR] 1.27, 95% CI 0.64 to 2.51), third (1.85, 95% CI 1.01 to 3.41), fourth (2.49, 95% CI 1.38 to 4.49), and fifth (3.12, 95% CI 1.61 to 5.08) quintiles.
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Death
All-cause mortality rates, expressed per 100 patient-years, were
0.19, 0.21, 0.54, 0.83, and 1.27 events per 100 patient-years in the 5
quintiles of LV mass (log-rank test, P<0.0001) (Figure 1, right). Figure 3 shows survival
curves in the 5 quintiles of LV mass. After control for the other
independent covariates (age and male gender), we found that a greater
LV mass was an independent predictor of all-cause death. As reported in
Table 4, subjects in the fifth quintile
of LV mass had a >4-fold RR for all-cause death compared with subjects
in the first quintile. The excess risk bordered on significance for
subjects in the fourth quintile.
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Predictive Value of LV Hypertrophy Defined by
Different Criteria
After adjustment for the other covariates in a
multivariate model, LV hypertrophy was
independently associated with risk for cardiovascular
complications regardless of the use of height-based indexes (51
g/m2.7; P<0.021, -2 Log L=2320.1),
gender-specific indexes adjusted for body surface area (125
g/m2 in men, 110 g/m2 in
women; P<0.004, -2 Log L=2317.0), or gender-independent
indexes adjusted for body surface area (125
g/m2; P<0.016, -2 Log L=2319.7).
When the classification of subjects into quintiles of LV mass replaced
the categorical definition of LV hypertrophy in the
equation, the resulting model provided a further improvement in the
prediction of risk estimate, expressed by a reduction in the -2 log L
value (2305.9, P<0.001 versus all models based on binary
partitions).
Men Versus Women
LV mass was significantly greater in men than in women, after
adjustment for both body surface area (116.2±31 versus 99.5±25
g/m2) and height (52.0±15 versus 47.6±13
g/m2.7, both P<0.0001). Event-free
survival analysis was also performed separately in men and
women. In a Cox regression model, LV hypertrophy (LV mass
125 g/m2 in men, 110
g/m2 in women) was an independent predictor of
cardiovascular morbidity in women (hazard ratio 1.99,
95% confidence interval 1.17 to 3.37) as well as in men (hazard ratio
1.54, 95% confidence interval 1.05 to 2.25). The independent impact of
increased LV mass on cardiovascular events was
significantly greater in women than it was in men. For each 1-SD
increment in LV mass (25 g/m2 in women, 31
g/m2 in men), the adjusted hazard ratio was 1.49
in women (95% CI 1.23 to 1.79) and 1.22 in men (95% CI 1.03 to 1.45;
P<0.02 for gender/LV mass index interaction).
LV Geometry
Cardiovascular event rate was higher in subjects
with LV concentric geometry (n=523), defined as a relative wall
thickness of 0.45, than in subjects with an eccentric geometry (3.53
versus 2.06 events/100 patient-years, P<0.01). However, the
prognostic value of LV concentric geometry, defined either as a
categorical or as a continuous variable, did not hold in a
multivariate Cox model (Table 3). The hazard
ratio for concentric geometry was 1.16 (95% CI 0.85 to 1.59) for
cardiovascular events and 1.26 (95% CI 0.69 to 2.31)
for all-cause deaths.
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Discussion |
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This study showed a strong linear relation between LV mass on echocardiography and subsequent cardiovascular morbidity and all-cause mortality rates in initially untreated and uncomplicated subjects with essential hypertension. The relation was statistically significant, clinically consistent, and persisted after correction for the influence of several traditional risk factors, including age, gender, diabetes, cigarette smoking, serum cholesterol level, and clinic and 24-hour ambulatory BP. An increased risk for cardiovascular disease was apparent for LV mass values of >105 g/m2 in men and >91 g/m2 in women, in large part below the traditional1 2 3 14 21 reference standards. The prevalence of subjects at increased risk ranged between 24% and 40%, depending on the criterion that was used, when binary definitions of LV hypertrophy were used, whereas it rose to 60% with the use of gender-specific LV mass quintiles. The use of quintiles significantly improved the goodness-of-fit of the multivariate model compared with the binary definitions, thus providing a better prediction of cardiovascular risk estimate.
Previous Studies
LV hypertrophy detected on
echocardiography is a widely established risk
factor for cardiovascular complications in
hypertension1 2 3 and in the general
population,4 5 as well as in a variety of clinical
settings.23 24 25 It is unknown whether the association
between LV mass and cardiovascular risk in hypertension
is continuous over a wide range of values and whether this association
holds also in the "normal" range of LV mass. Mensah et
al26 examined the prognostic value of LV mass in 193
subjects with essential hypertension stratified into 4 groups with
progressively greater LV mass. The 12-year incidence of
cardiovascular events was 64% in patients with
pretreatment LV mass of >174 g/m2 and 38% in
patients with pretreatment LV mass between 125 and 174
g/m2. However, the group at highest risk (LV mass
>174 g/m2) included only 11 subjects, and the
small number of events (50 total) did not allow a solid statistical
adjustment for the effect of several potential confounders. A recent
analysis of the Framingham Heart Study10 found an
increased LV mass in 26% of subjects. LV mass showed a linear
relationship with the rate of future cardiovascular
events, but when the subjects with LV hypertrophy were
stratified into 4 groups based on LV mass, the age- and risk
factor–adjusted hazard ratio was only 1.27 in the majority of subjects
(81% of the group) who had only a mild increase in LV mass. Hazard
ratio increased up to 1.75, 2.05, and 3.10 in the other 3 subsets,
which, however, represented only 19% of the subjects with
LV hypertrophy.10 Because only one third of
the studied population were hypertensive, these findings could not
provide a definite answer to the question regarding the prognostic
impact of a mild increase in LV mass in the specific setting of
essential hypertension.
Present Study
Despite the considerable literature on the adverse prognostic
value of LV hypertrophy in different clinical
settings,1 2 3 4 5 23 24 25 only a few
studies1 2 3 16 26 27 have been specifically conducted in
uncomplicated subjects with essential hypertension. Other studies have
been carried out with different populations of subjects, including the
general population,10 28 subjects undergoing cardiac
catheterization for presumed coronary artery
disease,23 29 survivors of myocardial
infarction,24 and subjects with renal
failure.25 Thus, more data are needed for subjects with
essential hypertension to better define the prognostic value of LV mass
in this important setting.
The general acceptance in the clinical practice of LV hypertrophy as a binary variable is derived from its documented prognostic value1 2 3 4 5 23 24 25 26 and from the convenience and easy applicability of the classification of LV mass values into 2 categories: normal and abnormal. Nevertheless, the distribution of LV mass is continuous in the general population,6 therefore making any definition of a cutoff value arbitrary. In our study, LV hypertrophy defined according to 3 different binary criteria was a significant independent predictor of prognosis in men and women with essential hypertension. However, an important contribution of the present study was that the stratification of subjects into quintiles of LV mass added precision to the risk estimate, as demonstrated by the further reduction of the -2 log L value in comparison with models based on binary partitions. Thus, stratification of LV mass values into quintiles appears to be more rewarding and equally easy to use for cardiovascular risk stratification than the use of LV hypertrophy as a yes/no variable.
The basic pathophysiological mechanisms underlying the association between LV mass and cardiovascular risk remain elusive.30 LV mass may be considered a time-integrated marker of exposure to high BP values and as a sensitive indicator of cardiac end-organ damage. It is well established30 that LV mass (1) increases myocardial oxygen consumption while reducing coronary blood flow reserve, (2) is associated with an increase in atherosclerotic lesions at cardiac and extracardiac levels, and (3) is associated with enhanced arrhythmogenesis.
Some other points deserve comment. First, the use of different categorical definitions of LV hypertrophy did not yield different results in terms of cardiovascular risk stratification. This finding reflects the high degree of correlation between the different indexes of LV mass and is in agreement with a recent study by Liao et al.29 Second, the adverse prognostic impact of increased LV mass was apparent in both genders but was significantly greater in women than in men. These data, which were obtained in uncomplicated subjects with essential hypertension, confirm and extend the results of another study by Liao et al, which was carried out in a hospital-based, predominantly black population of subjects with suspected coronary heart disease,31 in which the independent prognostic value of LV hypertrophy was considerably stronger in women than it was in men. The mechanisms underlying this gender difference remain unknown. Third, our study extends the existing literature2 16 27 31 32 33 by showing that the different LV geometric patterns seem to add little additional prognostic information to the overwhelming information provided by LV mass in hypertensive subjects.
Study Strengths and Limitations
The large number of cardiovascular events in
the present study allowed adjustment for the confounding effect of
several risk markers, including ambulatory BP. Our findings have been
obtained in initially untreated white subjects, so results may not be
extended to different racial groups or to subjects receiving
antihypertensive treatment at the time of the qualifying
echocardiographic study. Another limitation of the
study was the lack of an assessment of the serial changes in office BP,
ambulatory BP, and LV mass over time. In a previous study from our
group, the prognostic value of LV hypertrophy regression
remained significant after control for baseline LV mass and serial
changes in office and ambulatory BP.5
Clinical Implications
Our findings show a linear, powerful, and independent relation
between LV mass and cardiovascular risk in initially
untreated men and women with essential hypertension who were free from
overt cardiovascular disease. The stratification of
subjects into quintiles of LV mass provided a significant improvement
of risk estimate compared with the binary definition of LV
hypertrophy. An increased cardiovascular
risk was already detectable at LV mass values (>105
g/m2 in men and >91 g/m2
in women) considerably lower than the traditional upper normal limits,
thus allowing the identification of a substantially greater percentage
of individuals at an increased cardiovascular risk.
These findings may be of help in the clinical practice by allowing
better interpretation of the results of quantitative
echocardiography for cardiovascular
risk stratification in subjects with essential hypertension.
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Acknowledgments |
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This work was supported in part by grants from Associazione Umbra Cuore e Ipertensione, Perugia, Italy.
Received June 28, 1999; first decision July 16, 1999; accepted October 16, 1999.
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