Circ J 2008; 72: 538 – 544

Impact of Statin Therapy on Left Ventricular Function

and Carotid Arterial Stiffness in Patients
With Hypercholesterolemia

Yukio Mizuguchi, MD; Yoshifumi Oishi, MD; Hirokazu Miyoshi, MD;

Arata Iuchi, MD; Norio Nagase, MD; Takashi Oki, MD

Background Hypercholesterolemia is a well-established risk factor for the development of vascular events.
Statins have pleiotropic effects beyond reducing the low-density lipoprotein-cholesterol (LDL-C) concentration.
This study sought to determine whether treatment with pitavastatin affects latent regional left ventricular (LV)
systolic and diastolic dysfunction and carotid arterial stiffness in patients with hypercholesterolemia and preserved
LV ejection fraction (LVEF), using newly developed ultrasonic strain imaging and carotid ultrasonography.
Methods and Results A total of 30 patients with hypercholesterolemia (≥220 mg/dl for serum total cholesterol,
and/or ≥140 mg/dl for LDL-C) were randomized to either administration of pitavastatin (1 or 2 mg/day; n=15) or
no statin therapy (n=15) for 12 months. LV systolic and diastolic functions were evaluated by measuring trans-
mitral flow velocity, mitral annular motion velocity, and the myocardial strain and strain rate profiles using
pulsed Doppler, tissue velocity, and ultrasonic strain imaging. Subclinical atherosclerosis also was determined by
measuring the intima – media thickness (IMT) and stiffnessβof the left and right common carotid arteries using
B- and M-mode ultrasonography. During the follow-up period, the mean peak systolic strains of the LV posterior
and inferior walls increased from 39.2±15.9% to 51.5±17.7% (p<0.01) and 46.0±12.2% to 57.5±10.3% (p<0.01),
respectively, in the pitavastatin group compared with the no statin group. The mean peak early diastolic strain
rates of the LV posterior and inferior walls also increased from –6.5±2.9 s–1 to –9.5±2.8 s–1 (p<0.01) and –6.5±
2.5 s–1 to –9.1±2.7 s–1 (p<0.01), respectively, in the pitavastatin group. The stiffnessβdecreased from 5.6±2.5 to
4.1±0.8 (p<0.05) in the pitavastatin group, whereas there was no significant change in IMT.
Conclusions One year of pitavastatin treatment improved not only carotid arterial stiffness but also regional
LV systolic and diastolic function in patients with hypercholesterolemia and preserved LVEF. Ultrasonic strain
imaging has the potential to become a sensitive tool for detecting the effects of early medical intervention on
latent regional LV myocardial dysfunction in this patient population. (Circ J 2008; 72: 538 – 544)
Key Words: Carotid stiffness; Left ventricular function; Statins; Ultrasonic strain imaging

H
yperlipidemia is a well-established risk factor for
the development of cardiovascular disease and its
mortality.1 Recently, the 3-hydroxy-3-methylglu-
taryl coenzyme A reductase inhibitors, or statins, were
developed in the clinical setting, and have been demon-
strated to have pleiotropic effects in addition to their strong
lipid-lowering properties.2 Several large-scale primary and
secondary prevention trials have confirmed that cholesterol-
lowering therapy can reduce the rates of the first occurrence
and recurrence of coronary heart disease between 20% and
40%.3–6 Moreover, it has been reported that long-term statin
therapy improves aortic stiffness,7 blood pressure,8 and left
ventricular (LV) function.9–12 Widespread use of noninva-
sive investigations has enabled detailed evaluation of arte-
rial stiffness13 and LV systolic and diastolic function,14,15 so
(Received July 25, 2007; revised manuscript received November 14,
2007; accepted November 16, 2007)
Cardiovascular Section, Higashi Tokushima National Hospital,
National Hospital Organization, Tokushima, Japan
Mailing address: Yukio Mizuguchi, MD, Cardiovascular Section,
Higashi Tokushima National Hospital, National Hospital Organiza-
tion, 1-1 Ohmukai-kita, Ohtera, Itano-cho, Itano-gun, Tokushima
779-0193, Japan. E-mail: mizuguchi@higasitokusima.hosp.go.jp
All rights are reserved to the Japanese Circulation Society. For per-
missions, please e-mail: cj@j-circ.or.jp
in the present study, we used carotid ultrasonography and
newly developed ultrasonic strain imaging to determine
whether treatment with pitavastatin contributes to an im-
provement of carotid arterial stiffness and latent regional
LV myocardial function beyond the lipid-lowering effect in
patients with hypercholesterolemia and preserved LV ejec-
tion fraction (LVEF).
Methods
Study Design
Thirty consecutive patients with hypercholesterolemia
(≥220 mg/dl for serum total cholesterol, and/or ≥140 mg/dl
for low-density lipoprotein-cholesterol (LDL-C)) who
visited hospital between 2005 and 2006 were randomized to
either administration of pitavastatin (1 or 2 mg/day; 9 men,
6 women; mean age: 54±10 years) or no statin therapy (6
men, 9 women; mean age: 56±11 years) for 12 months. Ex-
clusion criteria were as follows: patients with any hypo-
lipidemic treatment within the past 6 months, patients with
inadequate echocardiographic recordings for proper mea-
surement, patients with clinically significant valvular dis-
ease, diabetes, cardiomyopathy, previously demonstrated
angina pectoris or myocardial infarction, hepatic dysfunc-
tion, renal failure, aortitis syndrome, previous stroke or

Circulation Journal Vol.72, April 2008

Statins Improve Arterial Stiffness and LV Function
transient ischemic attack, or infectious disease, and/or
patients who did not agree to participate in the present
study. Two patients in the statin group were receiving anti-
hypertensive therapy before this study, but none of the
other patients were taking any medications that could affect
hemodynamic or LV ventricular function.
The no statin group received diet and exercise therapy
without pitavastatin treatment during the follow-up period.
All patients were enrolled in a lifestyle intervention for
1 year. Exercise training included an individualized home
exercise program, including a minimum 150 min/week of
moderate-intensity physical activity. Dietary modification
included personal advice, making the total ingestion of
calories into standard body weight ×25 kCal in effect, and
abstaining from foods with high cholesterol content.
The normal group consisted of 20 subjects (12 men, 8
women; mean age: 54±8 years) who showed no significant
organic cardiovascular disease after routine echocardiogra-
phy and/or cardiac catheterization for chest pain, dyspnea,
or heart murmur on auscultation, and no systemic diseases
such as hypertension, diabetes, or hyperlipidemia.
A full clinical history and examination were performed
by a specialized physician. Baseline clinical data, cardio-
vascular risk factors, and cardiovascular medications were
recorded. A 12-lead electrocardiogram and routine echo-
cardiogram were reviewed.
All patients gave written informed consent, and the study
was approved by the institutional ethics committee because
this study was a preventive approach in patients with no
previous cardiovascular events, and the event rate is ex-
tremely low during the follow-up of 1 year.
Carotid Ultrasonography
We performed carotid ultrasonography at baseline and
after 12 months of pitavastatin or no statin therapy in all
30 patients. Ultrasound images were acquired using a 7.5-
MHz linear array transducer and Toshiba Power Vision
6000 ultrasound system (Toshiba Medical Systems, Tokyo,
Japan). Common carotid artery intima – media thickness
(IMT) was determined by high-resolution B-mode ultra-
sound using a technique validated by Simons et al13 (Fig 1,
Left). The right and left common carotid arteries were ex-
amined with the head tilted slightly upward in the mid-line
position. The transducer was manipulated so that the near
and far walls of the common carotid arteries were parallel to
the transducer footprint, and the lumen diameter was maxi-
mized in the longitudinal plane. The reference point for
measurement of the carotid IMT was the region where dila-
Circulation Journal Vol.72, April 2008
539
Fig 1. Representative B-mode ultrasound im-
ages of the common carotid artery used to mea-
sure intima – media thickness (IMT) (Left) and
stiffnessβ(Right). Maximum and mean IMTs
were determined as the greatest value (a) and
mean value [(a+b+c)/3] of the IMTs measured
from 3 contiguous sites at 1-cm intervals. Stiff-
nessβwas determined using the following equa-
tion: β= ln(SBP/DBP)/[(Ds – Dd)/Dd], where
Ds and Dd are the end-systolic and end-dias-
tolic diameters of the common carotid artery,
respectively; SBP and DBP are systolic and
diastolic blood pressures, respectively.
tion of the carotid bulb began. On that image, carotid IMT
was measured as the leading edges corresponding to the
transition zones between lumen – intima and media – adven-
titia over a length of 1 cm proximal to the reference point.
Maximum and mean IMTs were defined as the greatest and
mean values, respectively, of IMTs measured from 3 con-
tiguous sites at 1-cm intervals.
Stiffness of the common carotid artery was evaluated by
M-mode ultrasonography, and determined by the stiffness
index as validated by Hirai et al16 (Fig 1, Right); specifi-
cally, stiffnessβ= ln(SBP/DBP)/[(Ds – Dd)/Dd], where Ds
and Dd are the end-systolic and end-diastolic diameters of
the common carotid artery, respectively, and SBP and DBP
are the systolic and diastolic blood pressures, respectively.
Maximum and mean IMTs and stiffnessβs are expressed as
the means of both common carotid artery measurements.
Echocardiography
On the M-mode echocardiogram, the LVDd, LVDs,
maximal left atrial diameter, end-diastolic thickness of the
ventricular septum, and end-diastolic thickness of the LV
posterior wall were measured. The percent fractional short-
ening of the LV was determined using the following equa-
tion: percent fractional shortening of the LV (%) = [(LVDd –
LVDs)/LVDd] ×100.
LV end-diastolic and end-systolic volumes (EDV and
ESV, respectively) were calculated from the apical 2- and 4-
chamber views using a modified Simpson’s method. LVEF
was calculated as (LVEDV– LVESV)/LVEDV ×100.
The peak early diastolic velocity (E), the deceleration
time from the peak of the early diastolic wave to baseline
(E-DT), the peak atrial systolic velocity (A), and the E/A
ratio were assessed from the transmitral flow waves using
the pulsed Doppler method.
The mitral annular motion velocity was recorded in the
LV posterior wall site in the apical LV long-axis view
using the pulsed Doppler method. The peak systolic motion
velocity (Sw), peak early diastolic motion velocity (Ew),
peak atrial systolic motion velocity (Aw), and E/Ew were
determined.14 The acoustic power and filter frequencies of
the ultrasound system were set to the lowest values possible,
and the sample volumes (width of approximately 8 mm)
were set at the mitral annulus of the LV posterior wall.
Strain imaging data were collected from a transthoracic
approach using the same system equipped with a 2.5-MHz
transducer, and were acquired at a frame rate of 68 frames/s
and a sector angle of 30 degrees. The parasternal LV short-
axis view at the level of the chordae tendineae was used to
540 MIZUGUCHI Y et al.

Fig 2. Representative example of the recording of radial strain (Middle) and strain rate (Right) curves. Yellow squares
indicate the regions of interest (4×4 mm pixels) in the left ventricular (LV) posterior and inferior walls (PW and IW,
respectively) for the parasternal LV short-axis view at the level of the chordae tendineae (Left). C, LV contraction center
chosen at end-systole; A, the angle of motion 90±10° relative to the ultrasound beam, where Doppler calculations are not
possible; STs, peak systolic strain; SRs, peak systolic strain rate; SRe, peak early diastolic strain rate; SRa, peak atrial
systolic strain rate.

Table 1 Comparison of the Clinical Parameters Before and After Treatment With Pitavastatin in the Statin and No Statin
Groups

Statin No statin
Baseline 12 months Baseline 12 months
Age (years) 54±10 55±9 56±11 57±10
Height (cm) 164±12 164±12 160±8 160±8
Weight (kg) 67±8 66±8 64±10 64±11
BMI (kg/m2) 25±2 25±2 25±3 25±4
Gender (M/F) 9/6 – 6/9 –
SBP (mmHg) 129±14 120±18 128±16 127±17
DBP (mmHg) 80±11 75±12 73±8 73±9
PP (mmHg) 48±8 45±9 55±14 54±14
Current smoker (+/–) 5/10 – 4/11 –
Diabetes (+/–) 0/15 – 0/15 –
Antihypertensive treatment (+/–) 2/13 – 0/15 –
Total cholesterol (mg/dl) 223±35 188±18*,§ 224±25 219±29
Triglycerides (mg/dl) 175±79 140±68 158±71 147±56
HDL-cholesterol (mg/dl) 58±10 58±10 59±11 59±11
LDL-cholesterol (mg/dl) 144±29 126±22*,§ 152±18 153±18
Values are mean±SD. *p<0.05 vs no statin group after treatment, §p<0.01, vs statin group at baseline.
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure ; HDL, high-density lipopro-
tein; LDL, low-density lipoprotein.

evaluate the LV posterior and inferior walls (Fig 2, Left).
Myocardial strain measurements were performed with an
ultrasound system with tissue Doppler capabilities (Power
Vision 6000, Toshiba Medical Systems, Ohtawara, Japan)
equipped with a 2.5-MHz probe.17 Patients were placed in
the left lateral decubitus position, and the radial strain and
strain rate curves were recorded in the LV posterior and
inferior walls (Fig 2, Middle and Right). For interpretation
of the radial strain and strain rate measurements, after
setting the hypothetical center of LV contraction on the LV
short-axis view, the velocity data were corrected by the
actual Doppler angle (θ) of incidence for each sample
region (4×4 mm pixels) in the posterior and inferior walls
in the radial direction. A sample region was set along the
endocardial sites of the posterior and inferior walls with the
reference point for angle-correction placed at the center of
LV contraction. Semi-automated tissue tracking kept the
regions of interest overriding the subendocardium through-
out the cardiac cycle. Image analysis was performed offline
on a PC workstation using custom analysis software
(ApliQ, Toshiba Medical Systems), and the peak systolic
strain (STs), the peak systolic strain rate (SRs), peak early
diastolic strain rate (SRe), and peak atrial systolic strain
rate (SRa) were determined.
Statistical Analysis
Values are expressed as the mean ± SD. Differences in
the mean values between the statin and no statin groups dur-
ing the follow-up period were compared with the unpaired
Student’s t-test. The significance of the differences between
various parameters for the statin and no statin groups at
baseline and after treatment with pitavastatin were tested
using the paired t-test. A p-value <0.05 was considered
statistically significant.
Results
Clinical Characteristics
There were no significant differences in the clinical char-
acteristics at baseline between the groups (Table 1). Serum
total cholesterol and LDL-C concentrations were signifi-
cantly lower after pitavastatin therapy in the statin group,
whereas there were no significant changes in either variable
over time in the no statin group.
Echocardiography
There were no significant differences in the M-mode and
2-dimensional echocardiographic, transmitral flow veloci-
ty, and mitral annular motion velocity variables at baseline

Circulation Journal Vol.72, April 2008

Statins Improve Arterial Stiffness and LV Function 541

Table 2 Comparisons of M-Mode, 2-Dimensional, Pulsed Doppler Echocardiographic, and Tissue Velocity Parameters
Before and After Treatment With Pitavastatin in the Statin and No Statin Groups

Statin No statin
Baseline 12 months Baseline 12 months
End-diastolic ventricular septal thickness (mm) 9.1±1.6 9.4±1.5 9.3±1.3 9.6±1.3
End-diastolic LV posterior wall thickness (mm) 9.5±1.5 9.5±1.8 9.6±1.4 9.6±1.3
End-diastolic LV diameter (cm) 5.0±0.5 5.0±0.6 5.0±0.4 5.0±0.4
End-systolic LV diameter (cm) 2.8±0.4 2.6±0.4 2.8±0.6 2.7±0.4
Maximal left atrial diameter (cm) 3.7±0.6 3.8±0.6 3.8±0.5 3.7±0.5
Percent LV fractional shortening (%) 43±5 44±6 46±8 47±9
LV ejection fraction (%) 74±5 75±6 76±8 77±9
Transmitral flow velocity
Peak E velocity (cm/s) 0.68±0.1 0.74±0.1 0.71±0.2 0.70±0.2
Peak A velocity (cm/s) 0.63±0.1 0.68±0.1 0.66±0.1 0.68±0.1
E/A 1.1±0.2 1.2±0.4 1.1±0.4 1.1±0.4
E-DT (ms) 180±29 180±31 211±40 212±38
Mitral annular motion velocity
Ew (cm/s) 10.6±3 10.9±2 10.6±2 10.5±2
Aw (cm/s) 11.1±2 11.5±2 12.0±2 11.8±2
Sw (cm/s) 10.7±3 10.2±2 11.2±2 11.0±2
E/Ew 7.1±3 6.9±1 7.0±1 6.8±1
Values are mean±SD.
LV, left ventricle; peak E velocity, peak early diastolic velocity of transmitral flow; peak A velocity, peak atrial systolic velocity of
transmitral flow; E-DT, deceleration time from peak to baseline of the early diastolic transmitral flow velocity; Ew, peak early dia-
stolic mitral annular motion velocity; Aw, peak atrial systolic mitral annular motion velocity; Sw, peak systolic mitral annular motion
velocity; E/Ew, the ratio of E to Ew.

Table 3 Comparison of LV Wall Strain and Strain Rate Parameters Before and After Treatment With Pitavastatin in the
Statin and No Statin Groups

Statin No statin
Baseline 12 months Baseline 12 months
LV wall strain and strain rate
Peak systolic strain (%)
Posterior wall 39.2±16 51.5±18*,§ 42.1±18 37.9±14
Inferior wall 46.0±12 57.5±10*,§ 51.5±15 47.5±13
Systolic strain rate (s–1)
Posterior wall 2.9±1.1 2.9±0.8 2.7±0.9 2.7±0.8
Inferior wall 3.3±1.4 3.4±1.0 3.4±1.4 3.5±1.3
Early diastolic strain rate (s–1)
Posterior wall –6.5±2.9 –9.5±2.8*,§ –7.5±2.2 –7.8±2.3
Inferior wall –6.5±2.5 –9.1±2.7*,§ –7.2±1.8 –7.4±2.0
End-diastolic strain rate (s–1)
Posterior wall –2.5±1.2 –2.4±0.9 –2.8±0.9 –3.0±1.0
Inferior wall –3.3±1.4 –2.9±0.8 –3.1±1.5 –3.4±1.4
Values are mean±SD. *p<0.05 vs no statin group after treatment, §p<0.01 vs statin group at baseline.
Abbreviation see in Table 2.

between the 2 groups (Table 2). The mean peak systolic
strains and early diastolic strain rates for the LV posterior
and inferior walls at baseline in the statin and no statin
groups tended to be lower and were significantly lower (all
p<0.05), respectively, than the age-matched normal subjects
(peak systolic strain: 50.4±18.3% in the posterior wall,
53.2±18.2% in the inferior wall; peak early diastolic strain
rate: –9.0±2.1 s–1 in the posterior wall, –8.3±1.9 s–1 in the
inferior wall). The mean peak systolic strains and early
diastolic strain rates for the LV posterior and inferior walls
were significantly greater after pitavastatin therapy in the
statin group, but these variables did not change signifi-
cantly after diet and exercise therapy in the no statin group
(Table 3, Fig 3).
Carotid IMT and Stiffnessβ
There were no significant differences in the carotid max
and mean IMTs at baseline between the statin and no statin
groups, and between before and after treatment with
pitavastatin in the statin group (Table 4). Carotid stiffness
β was significantly lower after pitavastatin therapy in the
statin group, whereas there was no significant change in the
stiffness β between before and after treatment in the no
statin group.
Inter- and Intraobserver Variabilities
The interobserver variability in measurements of carotid
and ultrasonic strain imaging parameters was calculated as
the difference in 2 measurements performed in the same
patient by 2 different observers divided by the mean value.
The interobserver variability was 3.2–3.4%. Intraobserver
variability also was calculated as the difference between 2
measurements performed in the same patient by 1 observer
divided by the mean value. The intraobserver variability
was 2.9–3.0%.

Circulation Journal Vol.72, April 2008

542 MIZUGUCHI Y et al.

Fig 3. Representative example of the changes in radial strain (Left) and strain rate (Right) curves of the left ventricular
posterior wall before (Top) and after (Bottom) treatment with pitavastatin. The peak systolic strain (STs) and peak early
diastolic strain rate (SRe) are markedly increased after pitavastatin therapy. SRs, peak systolic strain rate; SRa, peak atrial
systolic strain rate.

Table 4 Comparison of Carotid Ultrasonographic Parameters Before and After Treatment With Pitavastatin in the Statin
and No Statin Groups

Statin No statin
Baseline 12 months Baseline 12 months
Max IMT (mm) 0.95±0.4 0.88±0.4 1.00±0.2 1.00±0.2
Mean IMT (mm) 0.90±0.3 0.81±0.3 0.89±0.1 0.84±0.2
Stiffness parameterβ 5.6±2.5 4.1±0.8*,§ 5.0±1.3 5.1±1.3
Values are mean±SD. *p<0.05 vs no statin group after treatment, §p<0.05 vs statin group at baseline.
IMT, intima-media thickness.

Mizuguchi et al investigated the relationship between

Discussion
In the present study, we demonstrated a clinically sub-
stantial benefit beyond the lipid-lowering properties of
pitavastatin therapy in patients with hypercholesterolemia.
Ultrasonic strain imaging was very useful compared with
conventional echocardiography in detecting minute im-
provements in regional LV function caused by pitavastatin.
In addition, pitavastatin led to improvement in carotid
artery stiffness.
Cardiovascular risk factors, including abdominal obesity,
dyslipidemia, glucose intolerance, and hypertension,18 con-
tribute to vascular endothelial dysfunction, resulting in the
development of atherosclerosis and coronary heart disease.19
With pulsed Doppler echocardiography, LV diastolic func-
tion can now be evaluated noninvasively by recording
transmitral flow and mitral annular or LV wall motion
velocities.14,20 Many studies have indicated that LV dias-
tolic dysfunction occurs before LV systolic dysfunction in
patients with hypertension,21 obesity,22 dyslipidemia,23 or
diabetes,24 even in the absence of overt cardiovascular
disease.
structural and functional changes in the carotid arteries and
LV myocardial function in patients with cardiovascular
risk factors, and found that LV relaxation is significantly
associated with carotid stiffness.25 Notably, ultrasonic strain
imaging revealed subclinical changes in intrinsic myocar-
dial deformation that could not be detected by the conven-
tional methods, including transmitral flow and mitral annu-
lar motion velocities, used to evaluate LV function.25–27
Statins have several pleiotropic effects, including anti-
inflammatory and immunomodulatory, antithrombotic, and
vascular effects, as well as their beneficial lipid-lowering
effects.28–30 In the clinical setting, it has been reported that
statins improve LV function. Sola et al reported that ator-
vastatin therapy for 12 months increases LVEF, reduces the
LV diameter, and improves several inflammatory markers
in patients with nonischemic heart failure.10 Node et al11
also found that simvastatin therapy for 14 weeks improves
LVEF, decreased the concentrations of plasma brain natri-
uretic peptide and inflammatory markers in patients with
idiopathic dilated cardiomyopathy. They suggested that the
anti-inflammatory and antioxidative effects of statins may

Circulation Journal Vol.72, April 2008

Statins Improve Arterial Stiffness and LV Function
play an important role in these outcomes. On the other
hand, Bountioukos et al reported that atorvastatin therapy
for 6 months dose not improve LVEF, but increases peak
systolic mitral annular motion velocity during low-dose
dobutamine infusion based on tissue Doppler imaging and
dobutamine stress echocardiography, and suggested that
the improvement in LV systolic function during dobutamine
stress can be attributed to the beneficial effect of atorvas-
tatin on flow-dependent coronary dilation and improvement
of endothelial function.12
In the present study, we demonstrated that pitavastatin
therapy improves not only regional LV systolic and diastol-
ic function, but also the carotid arterial stiffness parameter
β, although there is no significant change in IMT, in pa-
tients with hypercholesterolemia and preserved LVEF. In
general, atherosclerosis should be evaluated according to
the following 2 aspects: atherosis, which reflects structural
changes in the intima and media of vascular walls, and
sclerosis, which reflects changes in vascular stiffness or dis-
tensibility. The carotid IMT used in the present study is an
index of atherosis, and the stiffnessβis an index of sclero-
sis. Decreased distensibility of the arterial wall increases
SBP and decreases DBP, leading to increased LV afterload
and impairment of myocardial blood flow because of de-
creased coronary perfusion pressure. These abnormalities
are reflected in the decreased LV diastolic function preced-
ing LV systolic dysfunction.25,31 In an experimental study,
Ohtsuka et al reported that a decrease in the functional re-
serve of coronary arterial blood flow is induced by decreas-
ing arterial distensibility, resulting in impaired blood flow
in the endocardial layer.32
Previous findings and the results of the present study
suggest that statins may directly improve regional or global
LV myocardial function, and secondarily improve LV dias-
tolic function by increasing vascular elasticity. Therefore,
our results may be important in the consideration of the
diagnostic and therapeutic strategies aimed at cardiac pro-
tection in patients with hypercholesterolemia.
Conclusions
One-year pitavastatin treatment improved not only
carotid arterial stiffness but also regional LV systolic and
diastolic function in patients with hypercholesterolemia
and preserved LVEF. Ultrasonic strain imaging has the
potential to become a sensitive tool for detecting the effects
of early intervention on latent regional LV myocardial dys-
function in this patient population.
References
1. Pekkanen J, Linn S, Heiss G, Suchindran CM, Leon A, Rifkind BM,
et al. Ten-year mortality from cardiovascular disease in relation to
cholesterol level among men with and without preexisting cardiovas-
cular disease. N Engl J Med 1990; 322: 1700 – 1707.
2. Davignon J. Beneficial cardiovascular pleiotropic effects of statins.
Circulation 2004; 109(Suppl): 39 – 43.
3. Scandinavian Simvastatin Survival Study Group. Randomised trial
of cholesterol lowering in 4444 patients with coronary heart disease:
The Scandinavian Simvastatin Survival Study (4S). Lancet 1994;
344: 1383 – 1389.
4. The Long-Term Intervention with Pravastatin in Ischemic Disease
(LIPID) Study Group. Prevention of cardiovascular events and death
with pravastatin in patients with coronary heart disease and a broad
range of initial cholesterol levels. N Engl J Med 1998; 339: 1349 –
1357.
5. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M,
et al. Prevention of coronary and stroke events with atorvastatin in
Circulation Journal Vol.72, April 2008
543
hypertensive patients who have average or lower-than-average
cholesterol concentrations, in the Anglo-Scandinavian Cardiac Out-
comes Trial Lipid Lowering Arm (ASCOT-LLA): A multicentre
randomised controlled trial. Lancet 2003; 361: 1149 – 1158.
6. Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, Toyota
T, et al. Primary prevention of cardiovascular disease with pravastatin
in Japan (MEGA Study): A prospective randomised controlled trial.
Lancet 2006; 368: 1155 – 1163.
7. Kontopoulos AG, Athyros VG, Pehlivanidis AN, Demitriadis DS,
Papageorgiou AA, Boudoulas H. Long-term treatment effect of ator-
vastatin on aortic stiffness in hypercholesterolaemic patients. Curr
Med Res Opin 2003; 19: 22 – 27.
8. Ferrier KE, Muhlmann MH, Baguet JP, Cameron JD, Jennings GL,
Dart AM, et al. Intensive cholesterol reduction lowers blood pressure
and large artery stiffness in isolated systolic hypertension. J Am Coll
Cardiol 2002; 39: 1020 – 1025.
9. Bauersachs J, Hiss K, Fraccarollo D, Laufs U, Ruetten H. Simvastatin
improves left ventricular function after myocardial infarction in
hypercholesterolemic rabbits by anti-inflammatory effects. Cardio-
vasc Res 2006; 72: 438 – 446.
10. Sola S, Mir MQ, Lerakis S, Tandon N, Khan BV. Atorvastatin
improves left ventricular systolic function and serum markers of
inflammation in nonischemic heart failure. J Am Coll Cardiol 2006;
47: 332 – 337.
11. Node K, Fujita M, Kitakaze M, Hori M, Liao JK. Short-term statin
therapy improves cardiac function and symptoms in patients with
idiopathic dilated cardiomyopathy. Circulation 2003; 108: 839 – 843.
12. Bountioukos M, Rizzello V, Krenning BJ, Bax JJ, Kertai MD,
Vourvouri EC, et al. Effect of atorvastatin on myocardial contractile
reserve assessed by tissue Doppler imaging in moderately hypercho-
lesterolemic patients without heart disease. Am J Cardiol 2003; 92:
613 – 616.
13. Simons PCG, Algra A, Bots ML, Grobbee DE, van der Graaf Y.
Common carotid intima – media thickness and arterial stiffness:
Indicators of cardiovascular risk in high-risk patients: The SMART
study (Second Manifestations of ARTerial disease). Circulation
1999; 100: 951 – 957.
14. Oki T, Tabata T, Yamada H, Wakatuski T, Shinohara H, Nishikado
A, et al. Clinical application of pulsed Doppler tissue imaging for
assessing abnormal left ventricular relaxation. Am J Cardiol 1997;
79: 921 – 928.
15. Heimdal A, Stoylen A, Torp H, Skjaerpe T. Real-time strain rate
imaging of the left ventricle by ultrasound. J Am Soc Echocardiogr
1998; 11: 1013 – 1019.
16. Hirai T, Sasayama S, Kawasaki T, Yagi S. Stiffness of systemic arte-
ries in patients with myocardial infarction: A noninvasive method to
predict severity of coronary atherosclerosis. Circulation 1989; 80:
78 – 86.
17. Sade LE, Gorcsan J, Severyn DA, Edelman K, Katz WE. Usefulness
of angle corrected tissue Doppler to assess segmental left ventricular
function during dobutamine stress echocardiography in patients with
and without coronary artery disease. Am J Cardiol 2005; 96: 141 –
147.
18. Dandona P, Aljada A, Chaudhuri A, Mohanty P, Garg R. Metabolic
syndrome: A comprehensive perspective based on interactions
between obesity, diabetes, and inflammation. Circulation 2005; 111:
1448 – 1454.
19. Ross R. Atherosclerosis: An inflammatory disease. N Engl J Med
1999; 340: 115 – 126.
20. Kitabatake A, Inoue M, Saso M, Tanouchi J, Masuyama T, Abe H, et
al. Transmitral blood flow reflecting diastolic behavior of the left
ventricle in health and disease: A study by pulsed Doppler technique.
Jpn Circ J 1982; 46: 92 – 102.
21. Oki T, Tabata T, Yamada H, Wakatsuki T, Mishiro Y, Abe M, et al.
Left ventricular diastolic properties of hypertensive patients measured
by pulsed tissue Doppler imaging. J Am Soc Echocardiogr 1998; 11:
1106 – 1112.
22. Stoddard MF, Tseuda K, Thomas M, Dillon S, Kupersmith J. The
influence of obesity on left ventricular filling and systolic function.
Am Heart J 1992; 124: 694 – 699.
23. de las Fuentes L, Waggoner AD, Brown AL, Davila-Roman VG.
Plasma triglyceride level is an independent predictor of altered left
ventricular relaxation. J Am Soc Echocardiogr 2005; 18: 1285 –
1291.
24. Shishehbor MH, Hoogwerf BJ, Schoenhagen P, Marso SP, Sun JP,
Li J, et al. Relation of hemoglobin A1c to left ventricular relaxation in
patients with type 1 diabetes mellitus and without overt heart disease.
Am J Cardiol 2003; 91: 1514 – 1517.
25. Mizuguchi Y, Tanaka H, Oishi Y, Miyoshi H, Emi S, Ishimoto T, et
al. Predictive value of associations between carotid arterial sclerosis
544
and left ventricular diastolic dysfunction in patients with cardiovas-
cular risk factors. J Am Soc Echocardiogr 2007; 20: 806 – 812.
26. Vinereanu D, Nicolaides E, Tweddel AC, Madler CF, Holst B, Boden
LE, et al. Subclinical left ventricular dysfunction in asymptomatic
patients with type 2 diabetes mellitus, related to serum lipids and
glycated heamoglobin. Clin Sci 2003; 105: 591 – 599.
27. Fang ZY, Leano R, Marwick TH. Relationship between longitudinal
and radial contractility in subclinical diabetic heart disease. Clin Sci
2004; 106: 53 – 60.
28. Robinson JG, Smith B, Maheshwari N, Schrott H. Pleiotropic effects
of statins: Benefit beyond cholesterol reduction?: A meta-regression
analysis. J Am Coll Cardiol 2005; 46: 1855 – 1862.
29. Kawano H, Yano K. Pravastatin decreases blood pressure in hyper-
MIZUGUCHI Y et al.
tensive and hypercholesterolemic patients receiving antihypertensive
treatment. Circ J 2006; 70: 1116 – 1121.
30. Yoshihisa A, Iwai-Takano M, Yaoita H, Watanabe T, Maruyama Y.
Difference in early effects of statin therapy on coronary and forearm
flow reserve in postmenopausal hypercholesterolemic women. Circ J
2007; 71: 954 – 961.
31. Yambe M, Tomiyama H, Hirayama Y, Gulniza Z, Takata Y, Koji Y,
et al. Arterial stiffening as a possible risk factor for both atheroscle-
rosis and diastolic heart failure. Hypertens Res 2004; 27: 625 – 631.
32. Ohtsuka S, Kakihana M, Watanabe H, Sugishita Y. Chronically
decreased aortic distensibility causes deterioration of coronary perfu-
sion during increased left ventricular contraction. J Am Coll Cardiol
1994; 24: 1406 – 1414.
Circulation Journal Vol.72, April 2008