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Asymptomatic Left Ventricular Systolic Dysfunction in
Essential Hypertension
Prevalence, Determinants, and Prognostic Value
Paolo Verdecchia, Fabio Angeli, Roberto Gattobigio, Mariagrazia Sardone, Carlo Porcellati
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Abstract—Prevalence, determinants, and prognostic value of asymptomatic left ventricular systolic dysfunction (LVSD) in
uncomplicated subjects with essential hypertension are still incompletely known. We studied 2384 initially untreated
subjects with hypertension, no previous cardiovascular disease, and no symptoms or physical signs of congestive heart
failure (CHF). These subjects were studied at entry and followed for up to 17 years (mean 6.0). Asymptomatic LVSD
(ALVSD), defined by an echocardiographic ejection fraction ⬍50%, was found in 3.6% of subjects. Cigarette smoking
(P⫽0.013), increased left ventricular (LV) mass (P⫽0.001), and higher 24-hour heart rate (P⫽0.014) were independent
correlates of ALVSD. During follow-up, a first cardiovascular event occurred in 227 subjects, and 24 of these events
were hospitalizations for symptomatic CHF. Incidence of CHF per 100 persons per year was 0.12 in patients without
and 1.48 in patients with ALVSD (log-rank test P⫽0.0001). In a Cox model, after adjustment for age (P⫽0.0001), LV
mass (P⫽0.0001), and cigarette smoking (P⫽0.039), LVSD conferred a markedly increased risk for CHF (odds ratio,
9.99; 95% confidence interval, 3.67 to 27.2). Incidence of coronary (0.84 versus 0.62⫻100 person years) and
cerebrovascular (0.80 versus 0.62⫻100 person years) events did not differ (all P⫽NS) between subjects with and
without ALVSD. ALVSD is a potent and early marker of evolution toward severe CHF requiring hospitalization in
subjects with essential hypertension. (Hypertension. 2005;45:412-418.)
Key Words: heart failure 䡲 ventricular function, left 䡲 echocardiography 䡲 hypertrophy
䡲 blood pressure monitoring, ambulatory
H
ypertension is a potent risk factor for congestive heart
failure (CHF).1 According to the American College of
Cardiology/American Heart Association (ACC/AHA) practice guidelines for evaluation and management of chronic
CHF in the adult, all hypertensive subjects without symptoms
of CHF and without structural heart disease should be
classified as belonging to stage A, which denotes a high risk
for CHF, whereas those without symptoms of CHF but with
structural heart involvement denoted, for instance, by left
ventricular (LV) hypertrophy, should be classified as belonging to stage B.2 Development of overt CHF may be preceded
by a phase of asymptomatic LV systolic dysfunction
(ALVSD).3,4 Diagnosis of ALVSD is important because
treatment with angiotensin-converting enzyme (ACE) inhibitors may delay progression toward overt CHF in these
subjects.5,6 In the general population, prevalence of ALVSD
has been estimated at ⬇2% in most studies, a figure not
dissimilar from that of overt CHF.7–12
Many hypertensive subjects without symptoms or physical
signs of CHF should thus be considered for screening of
ALVSD, an argument that rises cost-effectiveness consider-
ations.12 However, important aspects including prevalence,
determinants, and prognostic value of ALVSD in the specific
setting of essential hypertension are poorly known because
most available studies have been performed in the general
population.7–12
Consequently, the present study was undertaken with the
aim to address the clinical value of ALVSD determined by
echocardiography in a large group of subjects with essential
hypertension, including the Progetto Ipertensione Umbria
Monitoraggio Ambulatoriale (PIUMA) database.13–15 We
sought to determine prevalence and determinants of ALVSD
and its contribution to the long-term risk of overt CHF and
other major cardiovascular adverse events.
Methods
The PIUMA study, initiated in June 1986, is a prospective observational registry in initially untreated subjects with essential hypertension.13–15 Entry criteria include an office blood pressure (BP)
ⱖ140 mm Hg systolic or 90 mm Hg diastolic on at least 3 visits and
absence of secondary causes of hypertension, previous cardiovascular disease, including CHF, and life-threatening conditions. During
each visit, 3 BP measurements were averaged for analysis. Overall
(Figure 1), 3010 subjects consecutively entered the PIUMA registry
Received November 20, 2004; first decision December 9, 2004; revision accepted December 20, 2004.
From the Department of Cardiovascular Disease (P.V., F.A., M.S., C.P.), R. Silvestrini Hospital, Perugia; and Division of Medicine (R.G.), Beato G.
Villa Hospital, Città della Pieve, Italy.
Correspondence to Paolo Verdecchia, MD, FACC, Dipartimento Malattie Cardiovascolari, Ospedale R. Silvestrini, Località S. Andrea delle Fratte,
06156 Perugia, Italy. E-mail [email protected]
© 2005 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000154822.37141.f6
412
Verdecchia et al
Prognosis of Systolic Dysfunction in Hypertension
413
experimental procedures including the echocardiographic study were
open to family doctors and hospital staff. Diuretics, ␤-blockers, ACE
inhibitors, calcium channel blockers and ␣1-blockers, alone or
combined, were the antihypertensive drugs most frequently used.
Contacts with family doctors and phone interviews with patients
were arranged to detect occurrence of major cardiovascular events.
End Points
For assessment of end points, hospital record forms and other source
documents of patients who died or experienced a cardiovascular
event were collected and reviewed in conference by the authors of
this study. Details about the international standard criteria used to
diagnose outcome events in the PIUMA study have been reported
previously.13,14 CHF has been defined as a documented hospitalization, or attendance in an acute care setting, for treatment of CHF.
Data Analysis
Figure 1. Selection of the study population. The number of participants is reported in the boxes.
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from June 12, 1986, to June 30, 2000, and 174 of these subjects were
lost to follow-up. Of the remaining 2836 subjects, 2724 had a
complete echocardiographic examination at entry, and in 2384 of
these subjects, the echocardiographic tracings were of good technical
quality to estimate LV structure and function. Age, sex distribution,
frequency of diabetes and cigarette smoking, and office and 24-hour
ambulatory BP did not differ (all P⫽NS) between the 626 subjects
with unavailable echocardiographic tracings and those admitted to
the present study.
Electrocardiography
Standard 12-lead ECG was recorded at 25 mm/s and 1 mV/cm
calibration. Subjects with complete right or left bundle branch block,
previous myocardial infarction, Wolff-Parkinson–White syndrome,
or atrial fibrillation were excluded from the analyses which tested the
relation of ECG LV hypertrophy to ALVSD and outcome. LV
hypertrophy was defined by using the Cornell/Strain index,15 a
modification of the Perugia score,14,16 to be considered positive for
LV hypertrophy in the presence of a modified Cornell voltage (sum
of S wave in lead V3 and R wave in lead aVL) ⬎2.4 mV in men or
⬎2.0 mV in women or a typical strain pattern.
Echocardiography
Details about reading procedures and reproducibility of linear
measures of LV mass in our laboratory have been reported previously.13 Linear measurements were made according to the American
Society of Echocardiography.17 LV volumes used to estimate ejection fraction (EF) were determined by using the Teichholz method.18
The EF threshold used for defining ALVSD was arbitrarily set to
50%.11 LV mass was calculated according to Devereux19 as follows:
(0.80⫻{1.04⫻[(septal thickness⫹LV internal diameter⫹posterior
wall thickness)3⫺(LV internal diameter3]}⫹0.6 g) and corrected by
height in meters at the power of 2.7.20 LV hypertrophy was defined
by an LV mass ⬎51.0 g/height (m2.7).
Ambulatory BP Monitoring
Ambulatory BP was recorded using an oscillometric device
(SpaceLabs 5200, 90202, and 90207; SpaceLabs), and measurements
were automatically taken every 15 minutes throughout the 24 hours.
Reproducibility of ambulatory BP readings has been assessed in a
subset of patients.21
Follow-Up
Follow-up of patients was mostly in charge of family doctors, in
cooperation with our hospital staff. Treatment was individualized
and based on lifestyle and pharmacological measures. Results of
Statistical analysis was performed using SPSS (SPSS) and SAS-Stat
(SAS Institute). In addition to standard descriptive and comparative
analyses, a multivariate logistic regression model was used to
estimate the independent correlates of ALVSD. All the variables
reported in Table 1 were tested in the model. For the subjects who
experienced multiple events, survival analysis was restricted to the
first event. Survival curves were estimated using Kaplan–Meier
product-limit method and compared with the Mantel (log-rank) test.
The effect of prognostic factors was evaluated by stepwise Cox
model.22 The following covariates were tested: age (years), sex
(women or men), systolic and diastolic BP (mm Hg), heart rate
(bpm), family history of cardiovascular disease at age ⬍55 in the
father or ⬍65 in the mother (no or yes), diabetes (no or yes), serum
cholesterol (mmol/L), serum triglycerides (mmol/L), smoking habits
(nonsmokers or current smokers), body mass index (kg/m2), antihypertensive treatment at the last follow-up visit before terminating
event or censoring (lifestyle measures, diuretics, ␤-blockers, ACE
inhibitors, calcium channel blockers, angiotensin II antagonists), LV
mass (g/height[m]2.7, ALVSD (no or yes), and year of entry into the
study (2-year intervals from 1986). To limit the impact of collinearity between the office and ambulatory values of BP and heart rate,
these covariates were included into the model either as office or
ambulatory values. The antihypertensive drug classes at follow-up
entered the model coded as 1 for present and 0 for absent. Diabetes
was defined by a fasting plasma glucose ⱖ7.0 mmol/L (126 mg/dL)
or antidiabetic drugs. Two-sided P values ⬍0.05 were considered
statistically significant.
Results
The clinical characteristics of subjects with and without
ALVSD are shown in Table 1. None of the subjects had
evidence of alcoholic, postpartum, or viral or restrictive
cardiomyopathy. Also, none of the subjects had segmental
wall motion abnormalities. A total of 75% of the subjects had
never been treated for hypertension, whereas previous treatment had been discontinued for ⬇4 weeks before entry
because of side effects, diagnostic tests, or unwillingness to
continue by the subjects in the remaining 25%. Diabetes was
found in 4.9% of participants, and 52% of these subjects were
receiving antidiabetic drugs.
Features of Subjects With LVSD
Prevalence of ALVSD was 3.6%. EF was 40% to 49% in 87%
of subjects, 30% to 39% in 9% of subjects and ⬍30% in 4%
of subjects. Compared with the subjects without ALVSD,
those with ALVSD were more frequently men and current
smokers. Office and 24-hour ambulatory BP levels were
increased in the subset with than in that without ALVSD. The
24-hour ambulatory heart rate was slightly but significantly
414
Hypertension
March 2005
TABLE 1.
Clinical Characteristics of Subjects With and Without ALVSD at Entry
Variable
Normal LV Systolic Function
(n⫽2299)
LVSD
(n⫽85)
50 (12)
49 (12)
0.68
53.5
67.1
0.01
26.7 (4)
26.9 (4)
0.59
23.9
40.0
0.001
Age, years
Men, %
Body mass index, kg⫻m⫺2
Current smokers, %
Diabetes, %
5.0
3.5
0.54
4.0 (6)
4.3 (6)
0.63
156/97 (19/10)
160/101 (20/11)
75 (11)
76 (13)
Duration of hypertension, years
Office BP, mm Hg
Office HR, bpm
24-Hour BP, mm Hg
P
Value
0.04/0.001
0.47
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137/87 (15/10)
142/90 (19/11)
24-Hour HR, bpm
75 (9)
77 (11)
0.002/0.009
Glucose, mmol/L
5.50 (1.1)
5.52 (1.4)
0.86
Creatinine, mol/L
85.6 (20)
88.6 (25)
0.22
Total cholesterol, mmol/L
5.56 (1.2)
5.42 (1.2)
0.21
HDL cholesterol, mmol/L
1.28 (0.3)
1.23 (0.4)
0.22
LDL cholesterol, mmol/L
3.58 (0.9)
3.65 (1.1)
0.56
Triglycerides, mmol/L
1.64 (1.1)
1.57 (0.7)
0.58
0.80
0.03
Uric acid, mmol/L
280 (82)
283 (85)
Interventricular septum (cm)
1.11 (0.2)
1.19 (0.3)
0.001
LV internal dimension (cm)
4.93 (0.5)
5.29 (0.6)
0.001
Posterior wall (cm)
1.00 (0.2)
1.07 (0.2)
0.001
0.001
2.7
LV mass (g/height⫻m )
48.3 (13)
59.0 (20)
Relative wall thickness
0.41 (0.9)
0.41 (0.9)
0.91
67.8 (8)
44.7 (6)
0.001
Electrocardiographic LVH (%)
15.0
26.3
0.008
Echocardiographic LVH (%)
36.3
61.2
0.0001
EF (%)
HR indicates heart rate; LVH, left ventricular hypertrophy.
higher in the subset with than without ALVSD. Age, body
mass index, diabetes, and known duration of hypertension did
not differ between the 2 groups. The greater LV mass in the
subjects with than in those without ALVSD resulted from a
greater wall thickness and internal diameter, without changes
in the relative wall thickness between the 2 groups. Prevalence of LV hypertrophy in the total sample was 15.4% at
ECG and 37.2% at echocardiography. All 56 subjects with
septum or posterior wall thickness ⱖ1.5 cm showed elevated
levels of BP (average office BP 170/105 mm Hg; average
24-hour BP 153/97 mm Hg), thus ruling out the possibility of
hypertrophic cardiomyopathy.
At the last follow-up visit before the terminating event or
censoring, diuretics were taken more frequently by subjects
with LVSD at entry than by those without (43% versus 32%;
P⫽0.03), whereas distribution of ACE inhibitors (38% versus
42%), ␤-blockers (17% versus 22%), calcium channel blockers (23% versus 20%), and angiotensin II antagonists (8.2%
versus 8.2%) did not differ between the 2 groups (all P⫽NS).
Correlates of ALVSD
In a logistic regression analysis, cigarette smoking
(P⫽0.013), echocardiographic LV mass (P⫽0.001), and
24-hour heart rate (P⫽0.014) showed a direct and independent relationship with ALVSD. Office heart rate did not
achieve significance. Figure 2, which reports the results of
analysis, allows visualization of the expected probability of
ALVSD for any given level of the significant covariates.
Incident Cardiovascular Events
The mean duration of follow-up was 6.0 years (range 0 to 17),
and the 2384 subjects contributed 14 204 person years of
follow-up. At the last follow-up contact, 35.2% of the
subjects were receiving lifestyle measures alone, 11.1%
diuretics or ␤-blockers alone or combined, 20.2% ACE
inhibitors or calcium channel blockers alone or combined,
and 33.5% other drug combinations. Overall, there were 227
first cardiovascular events, and the crude rate of events was
1.59 per 100 subjects per year. Of these first events, 24 were
hospitalizations for symptomatic CHF, and their crude rate
was 0.17 per 100 subjects per year (0.12 in the subjects
without and 1.48 in those with ALVSD). Three of these
subjects died shortly after hospitalization because of severe
CHF. Figure 3 displays the cumulative hazard and the crude
rate of overt CHF during follow-up in subjects with and
without ALVSD at entry. As shown in Figure 4, the crude rate
of total cardiovascular events was 3.16 and 1.55 per 100
subjects per year, respectively (log-rank test P⫽0.003), in the
subjects with and without ALVSD at entry. However, such a
difference was entirely explained by the difference between
Verdecchia et al
Prognosis of Systolic Dysfunction in Hypertension
415
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Figure 2. Results of logistic regression analysis. Probability of ALVSD in hypertensive patients in relation to cigarette smoking, mean
24-hour heart rate, and LV mass (LVM).
the groups in the incidence of overt CHF. In fact, neither the
cerebrovascular (58 cases of stroke and 26 cases of transient
ischemic attacks) nor the coronary (44 cases of acute myocardial infarction, 42 cases of unstable angina, and 6 cases of
sudden cardiac death) events showed any statistical differences between the 2 groups (Figure 3). The other 27 patients
developed occlusive arterial disease (n⫽19) or severe renal
failure requiring dialysis (n⫽8) as their first cardiovascular
event.
Multivariate Analysis
Table 2 shows the list of variables that achieved significance
in the multivariate analysis according to the Cox model.22
Age (P⫽0.0001), LV mass (P⫽0.001), and ALVSD
(P⫽0.0001) were the sole independent predictors of overt
CHF, and none of the other variables (see data analysis)
achieved statistical significance in modeling the multivariate
Figure 3. Cumulative hazard and crude rate of congestive heart
failure requiring hospitalization in hypertensive subjects with and
without ALVSD at entry.
hazard function. Table 2 shows the final multivariate model
with 3 covariates. End-diastolic LV internal diameter was a
significant predictor of CHF when it entered the equation
alone (P⫽0.0001) and after simultaneous adjustment for age
and ALVSD (P⫽0.014). However, its predictive value did
not remain significant (P⫽0.40) when LV mass entered the
equation. LV hypertrophy at ECG showed an independent
association with overt CHF after adjustment for age and
ALVSD (hazard ratio, 3.03; 95% confidence intervals, 1.26
to 7.29; P⫽0.013), but its predictive value did not remain
significant (P⫽0.27) after correction for LV mass.
Discussion
The present study provides the first assessment of prevalence,
determinants, and prognosis of ALVSD in a large population
of subjects with essential hypertension. In these subjects,
Figure 4. Total cardiovascular, coronary, and cerebrovascular
events in hypertensive subjects with and without ALVSD at entry.
416
TABLE 2.
Variable
Age
LV mass
ALVSD
Hypertension
March 2005
Independent Predictors of CHF (Cox Model)
Comparison
Adjusted Hazard Ratio
(95% Confidence Interval)
P
Value
1 SD (12 years)
2.87 (1.80–4.60)
0.0001
1 SD (13.8 g/height⫻m2.7)
1.58 (1.20–2.07)
0.001
Yes vs No
9.99 (3.67–27.2)
0.0001
prevalence of ALVSD, defined by an echocardiographic EF
⬍50%, was 3.6%, and the subjects with ALVSD showed a
9-fold higher risk of hospital admission for CHF over a mean
follow-up period of 6 years compared with those with normal
EF. The excess risk associated with ALVSD persisted after
simultaneous adjustment for age and LV mass, although these
results are supported by a relatively low number of outcome
events.
Previous Studies
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As discussed by Wang and et al,7 most of the available studies
that examined prevalence and clinical correlates of ALVSD
have been conducted in general population samples. In these
studies, prevalence of ALVSD ranged between 0.9% and
12.9%, depending on the clinical characteristics of the population and the EF values used to define ALVSD. The only
available report in patients with essential hypertension is a
cross-sectional analysis of the Genetic Epidemiology Network (HyperGEN) study,23 performed on 2086 hypertensive
subjects. In these subjects, EF was normal (⬎54%) in 86% of
participants and depressed in the remaining 14%. The inclusion of subjects with previous myocardial infarction or overt
CHF may contribute to explain the greater prevalence of
systolic dysfunction when compared with the present study.
Importantly, increased LV mass at echocardiography was a
strong and independent predictor of systolic dysfunction in
the HyperGEN and in our study.
Correlates of ALVSD
BP did not show any independent association with ALVSD.
However, increased LV mass could have mediated part of the
effects of pressure overload and other potential pathogenetic
factors on ALVSD. In a previous study, 24-hour ambulatory
systolic BP, gender, body mass index, postload insulin, and
insulin-growth factor-1 were independent determinants of LV
mass, and their combination explained 64% of the variability
of LV mass.24 In addition to LV mass, ambulatory heart rate
emerged as an independent correlate of ALVSD. Our findings
do not allow us to establish whether the association of heart
rate with ASVSD is a cause or effect relationship. In
experimental studies, pacing-induced tachycardia is a wellestablished technique to induce CHF.25 However, the impact
of tachycardia as a potential determinant of ALVSD is
scarcely known from epidemiological studies.7–12,23 In the
Echocardiographic Heart of England Screening Study, resting
heart rate was 71 bpm in the total sample of 3960 subjects and
77 bpm in the subset of individuals with ALVSD, but the
statistical significance of such a difference was not reported.8
In the present study, the availability of ambulatory heart rate
values may have facilitated the disclosure of the burden
attributable to heart rate over the 24 hours as a potential
determinant of ALVSD. Cigarette smoking was another
independent correlate of ALVSD. In the HyperGEN study, no
significant association was found between cigarette smoking
and LVSD.23 In the Framingham study, the risk of developing
overt CHF was higher in smokers than in never smokers by
65% in men and 56% in women.26 In the National Health and
Nutrition Examination Survey Epidemiologic Follow-Up
Study, the risk of overt CHF was 59% higher in smokers than
in nonsmokers.27 The basic mechanisms of the deleterious
effect of smoking on systolic function are scarcely known.
Cigarette smoking affects microvascular function,28 which
may be impaired in subjects with ALVSD.29
Natural History of ALVSD
The present study examined the relationship between
ALVSD and subsequent cardiovascular events in the specific
setting of uncomplicated subjects with essential hypertension.
In a previous study in hypertensive subjects, mean pulmonary
wedge pressure recorded invasively was an independent
predictor of mortality and of cardiovascular events.30 In the
present study, ALVSD was associated with a greater risk of
overt CHF, but not of coronary and cerebrovascular events.
Although the results of the echocardiographic study performed at entry were open to the treating physicians, awareness of echocardiographic EF did not lead to more frequent
use of ACE inhibitors in the subset with ALVSD. It should be
noted that the PIUMA study began in 1986, before the
widespread acceptance of ACE inhibitors in subjects with
ALVSD. In previous general population studies, ALVSD was
associated with an increased risk of cardiovascular mortality,31 all-cause mortality,31,32 and nonfatal cardiovascular
events.31,33 Several potential explanations, including different
definitions of ALVSD and the inclusion of subjects with
previous myocardial infarction and other comorbid conditions, may contribute to explain the variable prognostic
impact exerted by ALVSD on the different outcome events.
Indeed, overt CHF may be expected as a frequent complication in the natural history of ALVSD. In a cohort of elderly
participants to the Cardiovascular Health Study (mean age 72
years), 5.5% of subjects showed ALVSD, and the subsequent
incidence of CHF events approximated 3% per year.34 The
less stringent definition for overt CHF, which did not require
hospitalization, and the older age of the population may
contribute to explain the higher incidence of CHF in the
Cardiovascular Health Study than in the present study.
Study Limitations
We could not evaluate the prognostic impact of severe
systolic dysfunction because EF was ⬍30% only in 4% of
subjects with ALVSD. In a general population study, only 3%
of subjects without previous cardiovascular disease had an EF
ⱕ30%.10 In a report from the Framingham Heart Study,
prevalence of subjects with EF ⬍30% was 6%, but individuals with previous myocardial infarction and valvular disease
were not excluded.11 Furthermore, because our population is
exclusively composed of white subjects, extrapolation of
results to different ethnic groups may be problematic. In
addition, because only about one third of the subjects had
periodical echocardiographic examinations during follow-up,
Verdecchia et al
the prognostic impact of serial changes in LV anatomy and
function could not be determined. Two further limitations of
the present study are the lack of assessment of diastolic
dysfunction, which may be combined with a normal or
abnormal LV pump function,35 and the assessment of systolic
function at midwall level, which may also be impaired in
subjects with endocardial EF ⬎50%.36 Finally, because diagnosis of CHF had to be corroborated by hospitalization or
attendance for treatment in an acute care setting, we might
have missed subjects with acute heart failure who died before
attending the hospital and less severe subjects who were
treated by their family doctors at home. The present standard
definition of CHF is endorsed in large intervention trials in
the field of cardiovascular prevention.37,38
Perspectives
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ALVSD, defined by an echocardiographic EF ⬍50%, is
clinically important in asymptomatic subjects with essential
hypertension without overt CHF. In our study, its frequency
was 3.6%, and these subjects showed a 9-fold higher risk of
hospital admission for CHF when compared with the subjects
with normal EF. Once diagnosed, ALVSD should prompt
implementation of aggressive lifestyle and pharmacological
strategies to delay or prevent evolution toward symptomatic
CHF. Such strategies may be rewarding because treatment of
hypertension decreases the risk of CHF by ⬇50%,39 and ACE
inhibitors reduce the risk of overt CHF in patients with
ALVSD.5– 6 Appropriate strategies for ALVSD prevention in
hypertensive subjects with normal systolic function should be
investigated in future trials.
Acknowledgments
This work was supported in part by grants from Associazione Umbra
Cuore e Ipertensione, Perugia, Italy. We thank Francesca Saveri for
secretarial assistance and Mariano Cecchetti for nursing assistance.
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Asymptomatic Left Ventricular Systolic Dysfunction in Essential Hypertension:
Prevalence, Determinants, and Prognostic Value
Paolo Verdecchia, Fabio Angeli, Roberto Gattobigio, Mariagrazia Sardone and Carlo Porcellati
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Hypertension. 2005;45:412-418; originally published online January 17, 2005;
doi: 10.1161/01.HYP.0000154822.37141.f6
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