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ARTICLE
E n d o c r i n e
C a r e
Progressive Caloric Restriction Induces DoseDependent Changes in Myocardial Triglyceride
Content and Diastolic Function in Healthy Men
Sebastiaan Hammer,* Rutger W. van der Meer,* Hildo J. Lamb, Michael Schär, Albert de Roos,
Jan W. A. Smit, and Johannes A. Romijn
Departments of Endocrinology and Metabolism (S.H., R.W.v.d.M., J.W.A.S., J.A.R.) and Radiology (S.H., R.W.v.d.M., H.J.L., A.d.R.),
Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Russell H. Morgan Department of Radiology and Radiological
Science (M.S.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; and Philips Medical Systems (M.S.), Cleveland,
Ohio 44106
Context: In animal experiments, high plasma concentrations of free fatty acids (FFAs) are associated
with increased triglyceride (TG) stores in liver and heart, and impaired cardiac function. In humans
caloric restriction increases plasma FFA levels.
Objective: Our objective was to assess the effects of progressive caloric restriction on myocardial
and hepatic TG content and myocardial function.
Design: This was a prospective intervention study.
Participants: This study included 10 lean healthy men.
Interventions: Three-day partial (471 kcal/d) and complete starvation was performed.
Outcome Measures: Plasma levels of FFA, myocardial and hepatic TG content, and myocardial
function were calculated.
Results: Plasma FFA increased from 0.6 ⫾ 0.4 mmol/liter to 1.2 ⫾ 0.4 and to 1.9 ⫾ 0.7 mmol/liter,
after partial and complete starvation, respectively (P ⬍ 0.001). Myocardial TG content increased
from 0.35 ⫾ 0.14% to 0.59 ⫾ 0.27%, and 1.26 ⫾ 0.49%, respectively (P ⬍ 0.01). The ratio between
the early diastole and atrial contraction decreased from 2.2 ⫾ 0.4 to 2.1 ⫾ 0.4 (P ⫽ 0.7) and 1.8 ⫾
0.4, respectively (P ⬍ 0.01), and diastolic early deceleration from 3.4 ⫾ 0.7 ml/sec2 ⫻ 10⫺3 to 2.9 ⫾
0.5 and 2.8 ⫾ 0.9 ml/sec2 ⫻ 10⫺3, respectively (P ⬍ 0.05). Hepatic TG content decreased after partial
starvation (from 2.23 ⫾ 2.24% to 1.43 ⫾ 1.33%; P ⬍ 0.05) but did not change upon complete
starvation.
Conclusions: Progressive caloric restriction induces a dose-dependent increase in myocardial
TG content and a dose-dependent decrease in diastolic function in lean healthy men. Hepatic
TG content showed a differential response to progressive caloric restriction, indicating that
redistribution of endogenous TG stores is tissue specific. (J Clin Endocrinol Metab 93: 497–503,
2008)
lmost all endogenous triglycerides (TGs) are stored in adipose tissue to accommodate discrepancies between
whole body fat uptake and fat oxidation. However, a very small
A
proportion is stored in nonadipose tissues like the heart (1), the
liver (2), and skeletal muscle (3), especially in obesity and type 2
diabetes mellitus. There are indications that this storage of TG in
0021-972X/08/$15.00/0
Abbreviations: A, Atrial contraction; BMI, body mass index; E, early diastole; ECG, electrocardiogram; FA, fatty acid; FFA, free FA; LVEF, left ventricular ejection fraction; MRI,
magnetic resonance imaging; MRS, magnetic resonance spectroscopy; ppm, parts per
million; TC, total cholesterol; TE, echo time; TG, triglyceride; TR, repetition time; VLDL, very
low density lipoprotein.
Printed in U.S.A.
Copyright © 2008 by The Endocrine Society
doi: 10.1210/jc.2007-2015 Received September 7, 2007. Accepted November 13, 2007.
First Published Online November 20, 2007
* S.H. and R.W.v.d.M. contributed equally.
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Myocardial TG Content and Diastolic Function
nonadipose tissues is not merely an inert phenomenon but is
associated with more or less subtle physiological changes in
organ-specific functioning (4 – 8). In animal models there is an
inverse relation between myocardial TG content and myocardial
function. For example, myocardial lipid accumulation is associated with a decrease in left ventricular systolic function in obese
Zucker rats, and treatment with thiazolidinediones reduces myocardial TG content and improves left ventricular function (8).
The underlying mechanisms of the decrease in left ventricular
function are complex and are related to effects of fatty acid (FA)
derivatives, like fatty acyl-coenzyme A, ceramides, and diacylglycerol (4, 5, 7).
High plasma concentrations of free fatty acids (FFAs) may
result in excessive FA uptake in nonadipose tissues, such as the
liver and heart, which may affect normal organ function (7, 8).
However, in humans the relation between myocardial TG accumulation and myocardial function was difficult to study by
noninvasive methods because measurement of myocardial TG
content is challenging due to artifacts induced by cardiac and
respiratory motion. Recently, proton magnetic resonance
spectroscopy (MRS) of the heart was developed that enables
the measurement of myocardial TG content in humans in vivo
(1, 10 –13). Using this method, Reingold et al. (14) documented that fasting for 48 h increases plasma FFA levels and
myocardial TG content in healthy subjects, whereas myocardial TG content did not change after a single high fat meal. In
another, cross-sectional study, Kankaanpää et al. (12) showed
that increased levels of plasma FFA in obese subjects correlate
positively with myocardial TG content and inversely with cardiac function. However, both studies did not address the relation between myocardial function in relation to myocardial
TG content within the same subjects. In a recent study, we
documented that the use of a very low calorie diet increases
plasma FFA and myocardial TG content, associated with a
decrease in myocardial diastolic function (15). Therefore, it
appears that myocardial TG content is not fixed but varies
within the same subject according to physiological conditions.
It is yet unknown whether our recent findings of myocardial
flexibility can be extrapolated when caloric restriction is progressively increased. Therefore, the aim of the present study
was to extend the conditions of partial caloric restriction to
complete caloric restriction, i.e. complete starvation. For this
purpose we compared baseline observations with those obtained after 3-d partial starvation (471 kcal/d) and after 3-d
complete starvation with respect to plasma levels of FFA,
myocardial TG content, myocardial function, and hepatic TG
content.
J Clin Endocrinol Metab, February 2008, 93(2):497–503
was performed. An electrocardiogram (ECG) was made during the
first visit. Subjects with any aberrations on the ECG were excluded.
In addition, a 2-h 75 g oral glucose tolerance test was performed in the
fasted state, to exclude subjects suffering from diabetes mellitus (17).
Other exclusion criteria were: obesity (BMI ⬎ 30 kg/m2); liver disease
(increased plasma levels of alanine aminotransferase, aspartate aminotransferase, and/or ␥-glutamyl transferase ⬎ 2 SD above the reference value of our institution); renal disease (defined by plasma creatinine levels ⬎ 2 SD above the reference value of our institution); use
of any medication; and a history of (congenital) heart disease. Specifically, subjects with prior or present coronary artery disease (based
on medical history) or hypertension (defined as sitting systolic blood
pressure ⬎ 130 mm Hg and/or diastolic blood pressure ⬎ 85 mm Hg)
were excluded. Written informed consent was obtained from all participants before the study. The local ethics committee approved the
study.
Study design
The study consisted of three conditions. Baseline measurements were
made, while subjects followed a normal diet but abstained from alcohol
for 3 d (mean intake 2065 kcal/d). Subjects were admitted 4 h after the
last meal for measurement of plasma concentrations of glucose, insulin,
and lipids, and for evaluation by magnetic resonance imaging (MRI) and
MRS. The second measurement was performed after a 3-d period of
partial caloric restriction (471 kcal/d; Modifast Intensive, Nutrition &
Santé Benelux, Breda, The Netherlands). The third measurement was
performed after a 3-d period of complete starvation (0 kcal/d, only water
was allowed), after which subjects were again admitted for blood sampling and MRI/MRS evaluation. Plasma concentrations of FFA and insulin were used to assess study compliance (18). Between all study occasions, a washout period with a minimum of 14 d was acquired (19), and
the sequence of the second and third occasions was determined by balanced assignment.
1
H-MRS of the liver and the heart
All MRI/MRS measurements were performed on a 1.5-Tesla Gyroscan ACS-NT MRI scanner (Philips Medical Systems, Best, The Netherlands) in the supine position. Localized single voxel (2 ⫻ 2 ⫻ 2 cm for
the liver and 2 ⫻ 4 ⫻ 1 cm for the heart) spectra were recorded using a
body coil for radiofrequency transmission and a surface coil (Ø 17 cm)
for signal receiving. For the heart, the spectral volume was placed in the
interventricular septum on four-chamber and short axis images at end
systole, avoiding contamination with epicardial fat (Fig. 1). Data collection was double triggered using ECG triggering and navigator echoes
for compensation of respiratory motion as described earlier (13). For the
liver, voxel sites were matched at both study occasions, carefully avoiding blood vessels and bile ducts. To detect weak lipid signals, watersuppressed spectra with 128 averages for the heart and 64 for the liver
were collected. Spectral parameters were: a repetition time (TR) of 3000
msec, echo time (TE) of 26 msec, and 1024 data points over 1000 kHz
spectral width. In the same voxel, using the same parameters except for
a TR of 10,000 msec, unsuppressed spectra with four averages were
collected. Spectra were analyzed in the time domain, using Java-based
MR user interface software and prior knowledge files [version 2.2 (20)],
as described earlier (13). Peak estimates of lipid resonances of myocardial
TG at 1.3 parts per million (ppm) and 0.9 ppm were summed and calculated as a percentage of the unsuppressed water signal (TG content,
TG/water ⫻100).
Subjects and Methods
MRI of the heart
Subjects
There were 10 nonsmoking, healthy men included in this study
[age; mean ⫾ SD: 23.7 ⫾ 4.7 yr, range 20.8 –36.0 yr; body mass index
(BMI): 23.6 ⫾ 0.9 kg/m2]. Women were excluded because the hormonal status or contraceptive use may affect lipid metabolism (16).
The study population was partly based on a previous cohort (15). In
each subject, medical history was obtained, and physical examination
Imaging of the heart was performed using a body coil for radiofrequency transmission and a five-element synergy coil for signal receiving. To assess systolic function, the heart was imaged from apex
to base with 12–14 imaging levels (dependent on the heart size) in
short axis view using an ECG triggered, sensitivity encoding balanced
steady-state free procession sequence. Imaging parameters were a
field-of-view of 400 mm, a matrix size of 256 ⫻ 256, a slice thickness
J Clin Endocrinol Metab, February 2008, 93(2):497–503
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499
Left ventricular ejection fraction (LVEF) was
calculated for the assessment of systolic function. Furthermore, an ECG-gated gradientecho sequence with velocity encoding was performed to measure blood flow across the
mitral valve for the determination of left ventricular diastolic function (22, 23). Imaging
parameters included the following: a TE of 5
msec, a TR of 14 msec, a flip angle of 20°, a
slice thickness of 8 mm, a field-of-view of 350
mm, a matrix size of 256 ⫻ 256, a velocity
encoding of 100 cm/sec, and a scan percentage
of 80%. Flow velocities in early diastole (E)
and at atrial contraction (A) were measured,
and their peak flow ratio was calculated (E/A
ratio) using the FLOW analytical software
package (Medis) by defining a region of interest on the modulus images in all cardiac
phases. Furthermore, the mean deceleration of
the E wave and an estimation of left ventricular
filling pressures (E/Ea) (24) were measured.
All spectroscopic and functional analyses were
performed by an experienced observer,
blinded to the interventions. During MRI,
blood pressure and heart rate were measured
twice with an automatic device (Dinamap
DPC100X; Freiburg, Germany) and averaged
for analysis.
Assays
Glucose, total cholesterol (TC), and TG
were measured on a fully automated P800 analyzer (Roche, Almere, The Netherlands) and
insulin on a Immulite 2500 random access analyzer with a chemoluminescence immunoassay (Diagnostic Products Corp., Los Angeles,
CA). Coefficients of variation were less than
2% for glucose, TC, and TG, and less than 5%
for insulin. Plasma FFAs were measured using
a commercial kit (FFA-C; Wako Chemicals,
Neuss, Germany).
Statistical analysis
All statistical analyses were performed using SPSS, version 12.01 (SPSS, Inc., Chicago,
FIG. 1. Myocardial spectroscopic volume. Localization of the myocardial spectral voxel in the fourIL). Statistical comparisons among the three
chamber (A) and short axis views (B).
physiological conditions were made by repeated measures ANOVA. Pearson r values
were used for correlation analysis. Data are
of 10 mm, a slice gap of 0 mm, a flip angle of 35°, a TE of 1.67 msec,
shown as mean ⫾ SD. P ⬍ 0.05 (two tailed) was considered significant.
and a TR of 3.34 msec. Temporal resolution was 25–39 msec. End
Based on a previous report, we expected a decrease in diastolic early
diastolic and end systolic images were identified on all slices, and
deceleration. Therefore, P ⬍ 0.05 (one tailed) was considered signifendocardial contours were drawn using MASS post processing softicant for this parameter (15).
ware (Medis, Leiden, The Netherlands) as described previously (21).
TABLE 1. Metabolic response to progressive caloric restriction
Plasma concentrations
Glucose (mmol/liter)
Insulin (mU/liter)
FFAs (mmol/liter)
TGs (mmol/liter)
TC (mmol/liter)
Baseline
Partial starvation
Complete starvation
5.0 ⫾ 0.3
10.1 ⫾ 5.3
0.6 ⫾ 0.4
1.3 ⫾ 0.4
5.0 ⫾ 1.3
4.3 ⫾ 0.4a
8.0 ⫾ 3.7
1.2 ⫾ 0.4b
0.9 ⫾ 0.3a
5.1 ⫾ 1.4
3.9 ⫾ 0.5a
3.0 ⫾ 1.8a
1.9 ⫾ 0.7b
1.3 ⫾ 0.6
5.9 ⫾ 1.8a
Data are mean ⫾ SD. Blood samples were collected 4 h after the last meal.
a
P ⬍ 0.01 vs. baseline.
b
P ⬍ 0.001 vs. baseline.
500
Hammer et al.
Myocardial %TG (relative to baseline)
A
Myocardial TG Content and Diastolic Function
J Clin Endocrinol Metab, February 2008, 93(2):497–503
associated with a dose-dependent decrease in
plasma insulin levels. Simultaneously,
plasma concentrations of FFA increased dose
dependently from 0.6 ⫾ 0.4 mmol/liter to
1.2 ⫾ 0.4 mmol/liter after partial (P ⬍ 0.001)
and to 1.9 ⫾ 0.7 mmol/liter after complete
starvation (P ⬍ 0.001). Plasma TG levels decreased after partial starvation (from 1.3 ⫾
0.4 mmol/liter to 0.9 ⫾ 0.3 mmol/liter (P ⫽
0.009) but did not change upon complete
starvation (P ⫽ 0.677). TC increased from
5.0 ⫾ 1.3 mmol/liter at baseline to 5.1 ⫾ 1.4
mmol/liter after partial (P ⫽ 0.810) and to
5.9 ⫾ 1.8 mmol/liter after complete starvation (P ⫽ 0.005).
4
3
2
Triglycerides
1
Creatine
0
1.3
baseline
1.3
partial
starvation
1.3
complete
starvation
B 2.5
Myocardial TG (%)
2.0
1.5
*
ppm
Effects of progressive caloric
restriction on myocardial and hepatic
TG content
Myocardial TG content increased dose
dependently from 0.35 ⫾ 0.14% at baseline
to 0.59 ⫾ 0.27% after partial (P ⫽ 0.006)
and to 1.26 ⫾ 0.49% after complete starvation (P ⬍ 0.001; Fig. 2). Hepatic TG content
correlated with BMI at baseline (r ⫽ 0.67;
P ⫽ 0.033). Hepatic TG content significantly
decreased after partial starvation (from
2.24 ⫾ 2.24% to 1.43 ⫾ 1.33%; P ⫽ 0.031),
whereas it did not change after complete starvation (2.54 ⫾ 2.53%; P ⫽ 0.378; Fig. 3).
Effects of progressive caloric
restriction on myocardial function
(Table 2)
1.0
Systolic and diastolic blood pressure,
heart rate, and myocardial LVEF did not
*
change significantly during/after partial
and complete starvation, compared with
0.5
baseline. Furthermore, estimated left ventricular filling pressures were unchanged
after partial (8.8 ⫾ 3.8; P ⫽ 0.742) and
complete starvation (8.2 ⫾ 2.5; P ⫽ 0.299)
0
baseline
partial
complete
compared with baseline (9.3 ⫾ 2.6). Diastarvation
starvation
stolic E/A ratio decreased dose dependently
FIG. 2. Myocardial TG content at baseline, and after partial and complete starvation. Typical
from 2.2 ⫾ 0.4 at baseline to 2.1 ⫾ 0.4 after
proton spectra of myocardial TG content of one subject at baseline, and after partial and complete
partial starvation (P ⫽ 0.687) and to 1.8 ⫾
starvation scaled relative to baseline (A) and individual changes in myocardial TG content upon
complete starvation (n ⫽ 10) (B). Vertical lines represent mean ⫾ SD. *, P ⬍ 0.01 vs. baseline.
0.4 after complete starvation (P ⫽ 0.005).
E deceleration decreased dose dependently
from 3.4 ⫾ 0.7 ml/sec2 ⫻ 10⫺3 at baseline
Results
⫺3
to 2.9 ⫾ 0.5 ⫻ 10 ml/sec2 after partial (P ⫽ 0.036) and to 2.8 ⫾
0.9 after complete starvation (P ⫽ 0.032).
Metabolic effects of progressive caloric restriction
(Table 1)
Subject characteristics at baseline, after partial starvation, and
after complete starvation are shown in Table 1. Postabsorptive
Discussion
plasma glucose levels decreased from 5.0 ⫾ 0.3 mmol/liter at baseline to 4.3 ⫾ 0.4 mmol/liter after partial (P ⫽ 0.001) and to 3.9 ⫾
This study demonstrates that progressive caloric restriction in0.5 mmol/liter after complete starvation (P ⬍ 0.001). This was
creases myocardial TG content in lean healthy men. This increase
J Clin Endocrinol Metab, February 2008, 93(2):497–503
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501
Reingold et al. (14) documented that shortterm fasting leads to myocardial TG accumulation, although they did not document
8
effects on myocardial function. The current results, documenting dose-dependent
7
effects of caloric restriction on levels of
plasma FFA, myocardial TG content, and
6
diastolic function, extend these findings
and support the general concept that in5
creased myocardial TG content is associated with decreased myocardial function
4
(33). Alternatively, starvation profoundly
alters endogenous metabolic regulation
3
and other, yet undefined, metabolic effects
than merely increased levels of plasma FFA
*
2
and myocardial TG content, which may be
involved in explaining the reduction in
1
myocardial diastolic function. For example, caloric restriction might change cal0
cium homeostasis in the myocardium (34),
baseline
partial
complete
which affects myocardial diastolic function
starvation
starvation
(35).
FIG. 3. Hepatic TG content at baseline, and after partial and complete starvation. Individual
Transmitral flow velocities are load dechanges in hepatic TG content upon complete starvation (n ⫽ 10). Vertical lines represent mean ⫾
SD. *, P ⬍ 0.05 vs. baseline.
pendent and can be affected by changes in
intravascular volume. However, estimated
left ventricular filling pressures were unchanged upon progresis paralleled by decreased diastolic myocardial function. In adsive caloric restriction. Therefore, we believe that the observed
dition, the results document a dose-dependent effect between the
change in transmitral flow patterns results from a change in the
degree of caloric restriction and the myocardial effects. These
relaxation of the left ventricle. Caloric restriction enhances adobservations point to physiological variations in myocardial TG
ipose tissue lipolysis, reflected in increased levels of plasma FFA,
content and diastolic function. The effect of caloric restriction on
due to reduced insulin levels. Similar to our results in the heart,
redistribution of endogenous TG stores is tissue specific because
others found corresponding results of increased TG content of
we demonstrated differential effects of partial and complete starskeletal muscle after fasting (19, 25, 26). Starvation affects more
vation on liver TG content.
parameters of lipid metabolism because plasma FFAs stimulate
Different degrees of starvation were associated with a conthe hepatic production of very low density lipoprotein (VLDL),
siderable increase in plasma FFA levels, in accordance with prewhich is an important supplier for TG to the heart (36, 37).
vious observations (25, 26). These increased FFA levels reflect
Plasma FFA levels also increase during starvation and most likely
increased lipolysis of TG content in adipose tissue. Apparently,
will contribute to increased myocardial TG levels. However, the
during starvation myocardial FA uptake exceeds the requirerelative contribution of albumin-bound FAs vs. FAs derived from
ments of myocardial FA oxidation, resulting in increased TG
VLDL-TG to myocardial TG stores during caloric restriction
stores. Moreover, progressive caloric restriction has dose-depencannot be derived from the present data.
dent effects on myocardial TG accumulation and myocardial
We found a correlation between hepatic fat content and BMI,
function. However, a causal relationship between myocardial
in accordance with previous observations (2, 38). However, deTG content and myocardial function cannot be derived from the
spite the increase in the flux of plasma FFA to the liver, considpresent data.
ering the increased plasma FFA levels, hepatic TG content was
Our data are supported by animal experiments. In those studdecreased after partial starvation but was unchanged after comies excessive exposure of the myocardium to plasma FA is acplete starvation. In line with our results, Westerbacka et al. (9)
companied by increased storage of myocardial TGs, resulting in
previously documented that a low fat diet in moderately obese
the production of FA intermediates, and ultimately deteriorawomen decreases hepatic TG content. Because hepatic TG contions in myocardial function (8, 27, 28). Accordingly, it has been
tent is tightly regulated by the balance of hepatic FA uptake,
suggested that in obese subjects, subclinical diastolic dysfunction
hepatic FA oxidation, and output of VLDL-TG particles, it is
is due to changes in myocardial metabolism (29 –32). Kankaanpossible that this hepatic balance between FA uptake and TG
pää et al. (12) reported that alterations in left ventricular function
output is differentially affected by partial and complete starvain moderate obese subjects are associated with increased myotion. Nonetheless, our data indicate that progressive caloric recardial TG content, compared with lean subjects. Moreover,
striction differentially affects tissue-specific stores of TG in heart
Szczepaniak et al. (1) showed increased myocardial TG content
and liver, and prove that myocardial TG content and myocardial
in overweight and obese subjects, which was accompanied by
function vary depending on nutritional conditions, at least with
increased left ventricular mass. In accordance with our study,
Hepatic TG (%)
9
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Hammer et al.
Myocardial TG Content and Diastolic Function
J Clin Endocrinol Metab, February 2008, 93(2):497–503
TABLE 2. Effects of progressive caloric restriction on myocardial function
Systolic blood pressure (mm Hg)
Diastolic blood pressure (mm Hg)
Heart rate (bpm)
LVEF (%)
E/A ratio
E deceleration (ml/sec2 ⫻ 10⫺3)
Baseline
Partial starvation
Complete starvation
120 ⫾ 10
64 ⫾ 7
62 ⫾ 13
60 ⫾ 4
2.2 ⫾ 0.4
3.4 ⫾ 0.7
118 ⫾ 9
62 ⫾ 7
59 ⫾ 10
59 ⫾ 4
2.1 ⫾ 0.4
2.9 ⫾ 0.5b
122 ⫾ 12
61 ⫾ 5
65 ⫾ 10
60 ⫾ 6
1.8 ⫾ 0.4a
2.8 ⫾ 0.9b
Data are mean ⫾ SD. bpm, Beats per minute.
a
P ⬍ 0.01 vs. baseline.
b
P ⬍ 0.05 vs. baseline.
respect to progressive degrees of starvation. Additional studies
are required to elucidate to which extent these results can be
extrapolated to clinically relevant conditions like type 2 diabetes
mellitus and obesity.
In conclusion, progressive caloric restriction induces a dosedependent increase in myocardial TG content and a dose-dependent decrease in diastolic function in lean healthy men. Hepatic
TG content showed a differential response to progressive caloric
restriction, indicating that redistribution of endogenous TG
stores is tissue specific, at least in lean healthy men.
Acknowledgments
Address all correspondence and requests for reprints to: S. Hammer,
Department of Endocrinology and Metabolism (C4-R), Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
E-mail: [email protected].
Disclosure Summary: S.H., R.W.v.d.M., H.J.L., A.d.R., J.W.A.S.,
and J.A.R. have nothing to declare. M.S. is employed by Philips Medical
Systems. This author provided technical and intellectual input. The authors who were not employed by Philips Medical Systems had full control
of the inclusion of the data and information that might have presented
a conflict of interest for this author.
References
1. Szczepaniak LS, Dobbins RL, Metzger GJ, Sartoni-D’Ambrosia G, Arbique D,
Vongpatanasin W, Unger R, Victor RG 2003 Myocardial triglycerides and
systolic function in humans: in vivo evaluation by localized proton spectroscopy and cardiac imaging. Magn Reson Med 49:417– 423
2. Ishii M, Yoshioka Y, Ishida W, Kaneko Y, Fujiwara F, Taneichi H, Miura M,
Toshihiro M, Takebe N, Iwai M, Suzuki K, Satoh J 2005 Liver fat content
measured by magnetic resonance spectroscopy at 3.0 tesla independently correlates with plasminogen activator inhibitor-1 and body mass index in type 2
diabetic subjects. Tohoku J Exp Med 206:23–30
3. Sinha R, Dufour S, Petersen KF, LeBon V, Enoksson S, Ma YZ, Savoye M,
Rothman DL, Shulman GI, Caprio S 2002 Assessment of skeletal muscle triglyceride content by (1)H nuclear magnetic resonance spectroscopy in lean and
obese adolescents: relationships to insulin sensitivity, total body fat, and central adiposity. Diabetes 51:1022–1027
4. Lee Y, Hirose H, Ohneda M, Johnson JH, McGarry JD, Unger RH 1994 ␤-cell
lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of
obese rats: impairment in adipocyte-␤-cell relationships. Proc Natl Acad Sci
USA 91:10878 –10882
5. Shimabukuro M, Zhou YT, Levi M, Unger RH 1998 Fatty acid-induced ␤ cell
apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci USA 95:
2498 –2502
6. Shimabukuro M, Higa M, Zhou YT, Wang MY, Newgard CB, Unger RH
1998 Lipoapoptosis in ␤-cells of obese prediabetic fa/fa rats. Role of serine
palmitoyltransferase overexpression. J Biol Chem 273:32487–32490
7. Unger RH, Orci L 2001 Diseases of liporegulation: new perspective on obesity
and related disorders. FASEB J 15:312–321
8. Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci
L, Unger RH 2000 Lipotoxic heart disease in obese rats: implications for
human obesity. Proc Natl Acad Sci USA 97:1784 –1789
9. Westerbacka J, Lammi K, Hakkinen AM, Rissanen A, Salminen I, Aro A,
Yki-Jarvinen H 2005 Dietary fat content modifies liver fat in overweight nondiabetic subjects. J Clin Endocrinol Metab 90:2804 –2809
10. den Hollander JA, Evanochko WT, Pohost GM 1994 Observation of cardiac
lipids in humans by localized 1H magnetic resonance spectroscopic imaging.
Magn Reson Med 32:175–180
11. Felblinger J, Jung B, Slotboom J, Boesch C, Kreis R 1999 Methods and reproducibility of cardiac/respiratory double-triggered (1)H-MR spectroscopy
of the human heart. Magn Reson Med 42:903–910
12. Kankaanpää M, Lehto HR, Parkka JP, Komu M, Viljanen A, Ferrannini E,
Knuuti J, Nuutila P, Parkkola R, Iozzo P 2006 Myocardial triglyceride content
and epicardial fat mass in human obesity: relationship to left ventricular function and serum free fatty acid levels. J Clin Endocrinol Metab 91:4689 – 4695
13. van der Meer RW, Doornbos J, Kozerke S, Schar M, Bax JJ, Hammer S, Smit
JW, Romijn JA, Diamant M, Rijzewijk LJ, de Roos A, Lamb HJ 2007 Metabolic imaging of myocardial triglyceride content: reproducibility of 1H MR
spectroscopy with respiratory navigator gating in volunteers. Radiology 245:
251–257
14. Reingold JS, McGavock JM, Kaka S, Tillery T, Victor RG, Szczepaniak LS
2005 Determination of triglyceride in the human myocardium by magnetic
resonance spectroscopy: reproducibility and sensitivity of the method. Am J
Physiol Endocrinol Metab 289:E935–E939
15. van der Meer RW, Hammer S, Smit JW, Frolich M, Bax JJ, Diamant M,
Rijzewijk LJ, de Roos A, Romijn JA, Lamb H 2007 Short term caloric restriction induces accumulation of myocardial triglycerides and decreases left ventricular diastolic function in healthy subjects. Diabetes 56:2849 –2853
16. ESHRE Capri Workshop Group 2006 Hormones and cardiovascular health in
women. Hum Reprod Update 12:483– 497
17. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus
2003 Report of the Expert Committee on the Diagnosis and Classification of
Diabetes Mellitus. Diabetes Care 26(Suppl 1):S5–S20
18. Klein S, Sakurai Y, Romijn JA, Carroll RM 1993 Progressive alterations in
lipid and glucose metabolism during short-term fasting in young adult men.
Am J Physiol 265(5 Pt 1):E801–E806
19. Johnson NA, Stannard SR, Rowlands DS, Chapman PG, Thompson CH,
O’Connor H, Sachinwalla T, Thompson MW 2006 Effect of short-term starvation versus high-fat diet on intramyocellular triglyceride accumulation and
insulin resistance in physically fit men. Exp Physiol 91:693–703
20. Vanhamme L, van den BA, Van Huffel S 1997 Improved method for accurate
and efficient quantification of MRS data with use of prior knowledge. J Magn
Reson 129:35– 43
21. Pattynama PM, Lamb HJ, van der Velde EA, van der Wall EE, de Roos A 1993
Left ventricular measurements with cine and spin-echo MR imaging: a study
of reproducibility with variance component analysis. Radiology 187:261–268
22. Hartiala JJ, Mostbeck GH, Foster E, Fujita N, Dulce MC, Chazouilleres AF,
Higgins CB 1993 Velocity-encoded cine MRI in the evaluation of left ventricular diastolic function: measurement of mitral valve and pulmonary vein flow
velocities and flow volume across the mitral valve. Am Heart J 125:1054 –1066
23. Lamb HJ, Beyerbacht HP, van der Laarse A, Stoel BC, Doornbos J, van der
Wall EE, de Roos A 1999 Diastolic dysfunction in hypertensive heart disease
is associated with altered myocardial metabolism. Circulation 99:2261–2267
24. Paelinck BP, de Roos A, Bax JJ, Bosmans JM, Der Geest RJ, Dhondt D, Parizel
PM, Vrints CJ, Lamb HJ 2005 Feasibility of tissue magnetic resonance imag-
J Clin Endocrinol Metab, February 2008, 93(2):497–503
25.
26.
27.
28.
29.
30.
31.
ing: a pilot study in comparison with tissue Doppler imaging and invasive
measurement. J Am Coll Cardiol 45:1109 –1116
Stannard SR, Thompson MW, Fairbairn K, Huard B, Sachinwalla T, Thompson CH 2002 Fasting for 72 h increases intramyocellular lipid content in
nondiabetic, physically fit men. Am J Physiol Endocrinol Metab 283:E1185–
E1191
Wietek BM, Machann J, Mader I, Thamer C, Haring HU, Claussen CD,
Stumvoll M, Schick F 2004 Muscle type dependent increase in intramyocellular lipids during prolonged fasting of human subjects: a proton MRS study.
Horm Metab Res 36:639 – 644
Christoffersen C, Bollano E, Lindegaard ML, Bartels ED, Goetze JP, Andersen
CB, Nielsen LB 2003 Cardiac lipid accumulation associated with diastolic
dysfunction in obese mice. Endocrinology 144:3483–3490
Ouwens DM, Boer C, Fodor M, de Galan P, Heine RJ, Maassen JA, Diamant
M 2005 Cardiac dysfunction induced by high-fat diet is associated with altered
myocardial insulin signalling in rats. Diabetologia 48:1229 –1237
Sharma S, Adrogue JV, Golfman L, Uray I, Lemm J, Youker K, Noon GP,
Frazier OH, Taegtmeyer H 2004 Intramyocardial lipid accumulation in the
failing human heart resembles the lipotoxic rat heart. FASEB J 18:1692–1700
de Las FL, Waggoner AD, Brown AL, Davila-Roman VG 2005 Plasma triglyceride level is an independent predictor of altered left ventricular relaxation.
J Am Soc Echocardiogr 18:1285–1291
Diamant M, Lamb HJ, Groeneveld Y, Endert EL, Smit JW, Bax JJ, Romijn JA,
de Roos A, Radder JK 2003 Diastolic dysfunction is associated with altered
jcem.endojournals.org
32.
33.
34.
35.
36.
37.
38.
503
myocardial metabolism in asymptomatic normotensive patients with wellcontrolled type 2 diabetes mellitus. J Am Coll Cardiol 42:328 –335
Peterson LR, Herrero P, Schechtman KB, Racette SB, Waggoner AD, KisrievaWare Z, Dence C, Klein S, Marsala J, Meyer T, Gropler RJ 2004 Effect of
obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation 109:2191–2196
McGavock JM, Victor RG, Unger RH, Szczepaniak LS 2006 Adiposity of the
heart, revisited. Ann Intern Med 144:517–524
Han X, Cheng H, Mancuso DJ, Gross RW 2004 Caloric restriction results in
phospholipid depletion, membrane remodeling, and triacylglycerol accumulation in murine myocardium. Biochemistry 43:15584 –15594
Zile MR, Brutsaert DL 2002 New concepts in diastolic dysfunction and diastolic heart failure. Part II: causal mechanisms and treatment. Circulation
105:1503–1508
Goudriaan JR, Tacken PJ, Dahlmans VE, Gijbels MJ, van Dijk KW, Havekes
LM, Jong MC 2001 Protection from obesity in mice lacking the VLDL receptor. Arterioscler Thromb Vasc Biol 21:1488 –1493
Sakai J, Hoshino A, Takahashi S, Miura Y, Ishii H, Suzuki H, Kawarabayasi Y,
Yamamoto T 1994 Structure, chromosome location, and expression of the human
very low density lipoprotein receptor gene. J Biol Chem 269:2173–2182
Westerbacka J, Corner A, Tiikkainen M, Tamminen M, Vehkavaara S, Hakkinen AM, Fredriksson J, Yki-Jarvinen H 2004 Women and men have similar
amounts of liver and intra-abdominal fat, despite more subcutaneous fat in
women: implications for sex differences in markers of cardiovascular risk.
Diabetologia 47:1360 –1369