Sharma, S. Et Al. Intramyocardial Lipid Accumulation in The Failing Human Heart Resembles The Lipotoxic Rat Heart. FASEB J. 18, 1692-1700

See discussions, stats, and author profiles for this publication at:
https://www.researchgate.net/publication/8197529
Sharma, S. et al. Intramyocardial lipid accumulation

in the failing human heart resembles the lipotoxic rat
heart. FASEB J. 18, 1692-1700
Article in The FASEB Journal · November 2004

Impact Factor: 5.04 · DOI: 10.1096/fj.04-2263com · Source:
PubMed
SEE PROFILE
Ivan P Uray University of Texas MD Anderson
Cancer Ce...
CITATIONS
37 PUBLICATIONS 1,186 CITATIONS
405
READS SEE PROFILE
86
Heinrich Taegtmeyer University of Texas

Health Science Center a...
9 authors, including: 331 PUBLICATIONS 14,299 CITATIONS
Leonard Golfman University of Texas MD SEE PROFILE
Anderson Cancer Ce...
SEE PROFILE
George P Noon Baylor

College of Medicine

The FASEB Journal • Research
Communication
Intramyocardial lipid accumulation in the failing human
heart resembles the lipotoxic rat heart
SAUMYA SHARMA,* JULIA V. ADROGUE,* LEONARD GOLFMAN,* IVAN URAY,† JOHN LEMM,*
KEITH YOUKER,‡ GEORGE P. NOON,‡ O. H FRAZIER,§ AND HEINRICH TAEGTMEYER*,§,1
*Department of Internal Medicine, Division of Cardiology, † Department of Integrative Biology and
Pharmacology, University of Texas-Houston Medical School, Houston, Texas, USA; ‡ Department of
Cardiovascular Surgery, Baylor College of Medicine, Houston, Texas, USA; and § Texas Heart Institute and St.
Luke’s Episcopal Hospital, Houston, Texas, USA

ntramyocardial lipid accumulation in the failing human
heart resembles the lipotoxic rat heart. FASEB J. 1 8,
ABSTRACT In animal models of lipotoxicity, accumulation
1692–1700 (2004)
of triglycerides within cardiomyocytes is associated with
contractile dysfunction. However, whether intramyocardial
lipid deposition is a feature of human heart failure remainsKey Words: triglyceride accumulation contractile dysfunction
to be established. We hypothe- sized that intramyocardial
lipid accumulation is a common feature of non-ischemicnon-ischemic heart failure lipotoxicity
heart failure and is associated with changes in gene
expression similar to those found in an animal model of
The accumulation of triglyceride in the heart, caused by a
lipotoxicity. Intramyocar- dial lipid staining with oil red O
mismatch between the uptake and the oxidation of fatty acids, is
and gene expression analysis was performed on heart tissue
associated with a number of pathophysio-
from 27 patients (9 female) with non-ischemic heart failure.
logic conditions. Patients with congenital lipodystrophy, a rare
We determined intramyocardial lipid, gene expression,
disorder in which the absence of adipocytes results in the
and contractile function in hearts from 6 Zucker diabetic
accumulation of lipid of non-adipose tissues, or with inherited
fatty (ZDF) and 6 Zucker lean (ZL) rats. Intramyocardial
mitochondrial fatty acid oxidation defects develop premature
lipid overload was present in 30% of non-ischemic failing
cardiomyopathy (1, 2). In animal models of obesity and
hearts. The highest levels of lipid staining were observed in
diabetes, triglyceride accumulation within cardiomyocytes is
patients with diabetes and obesity (BMI>30).
associated with impaired contractile function (2–4). Treatment
Intramyocardial lipid deposition was associated with an
with insulin-sensitizing drugs not only reduces the deposition of
up-regulation of peroxisome proliferator-activated
lipid in the myocardium but reverses contractile dysfunction in
receptor (PPAR ) -regulated genes, myosin heavy chain
lipotoxic rats, suggesting that intramyocardial triglyceride
(MHC- ), and tumor necrosis factor (TNF- ).
accumulation is deleteri- ous (4).
Intramyocardial lipid overload in the hearts of ZDF rats
Although it is unclear how lipids induce cardiac
was associated with contractile dysfunction and changes in
dysfunction, accumulation of intramyocardial triglyceride is
gene expression similar to changes found in failing human
associated with altered gene expression (2). Specifically, there
hearts with lipid overload. Our findings identify a
is increased expression of the peroxisome
subgroup of patients with heart failure and severe metabolic
proliferator-activated receptor (PPAR ) -regulated genes (2–4).
dysregulation characterized by intramyocardial
PPAR is a nuclear receptor that, when activated by long chain
triglyceride overload and changes in gene expression that
fatty acids, induces the expression of proteins that increase the
are associated with contractile dysfunction.—Sharma, S.,
uptake and oxidation of fatty acids (5). Cardiac-specific
Adrogue, J. V., Golfman, L., Uray, I., Lemm, J., Youker, K.,
overexpression of PPAR induces cardiac dysfunction in mice
Noon, G. P., Frazier, O. H., Taegtmeyer, H.
exposed to high circulating fatty acid levels (6). Phar-
macologic activation of PPAR in the pressure-overloaded rat can induce cell death (2, 4, 11). Collectively, the term cardiac
heart contributes to contractile dysfunction (7). In patients with lipotoxicity refers to this constellation of altered fatty acid
diabetes and obesity, expression of the inflammatory cytokine
tumor necrosis factor (TNF- ) is increased in lipid-overloaded
tissues and correlates positively with insulin resistance (8, 9). 1
Correspondence: Department of Internal Medicine, Divi- sion

TNF- can directly cause contractile dysfunction in the heart andof Cardiology, University of Texas Houston-Medical School, 6431
has been implicated in pathologic remodeling in heart failure Fannin, MSB 1.246, Houston, TX 77030, USA. E-mail:
(10). The accumulation of excess lipid within cardiomyocytes Heinrich.Taegtmeyer@uth.tmc.edu
may lead to the production of toxic lipid intermediates, which doi: 10.1096/fj.04-2263com
1692 0892-6638/04/0018-1692 © FASEB

using metabolism, intramyocardial lipid overload, and contractile dysfunction.
Excluding patients with inherited defects in fatty acid oxidation or congenital lipodystrophy, it is unknown whether
intramyocardial lipid accumulation is associated with cardiac dysfunction in humans. The objective of this study
was to examine intramyocardial triglycer-
a Leitz Microlumina digital camera. Oil red O staining was quantified using Image Pro Plus software with color cube-based
selection criteria to ensure that only stained regions were counted, as described previously (3).
Using this method, we assigned patients into three groups based on area-intensity of staining in heart tissue sections. Low lipid
deposition was defined as 0.00 to 0.60 arbitrary units (AU) of oil red O staining. Moderate lipid deposition i de accumulation
and gene expression in patients with non-ischemic heart failure and to compare the results with the Zucker diabetic
fatty (ZDF) rat, an animal model of lipotoxicity. We found that patients with heart
was defined as 0.61 to 1.00 AU. High lipid deposition was defined as 1.00 AU. Figure 1a shows representative pho-
tomicrographs of low, moderate, and high intramyocardial lipid deposits.
failure and diabetes and/or obesity exhibited significant intramyocardial lipid deposition associated with a
Candidate genes
gene expression profile similar to that of the ZDF rat heart.
RNA was isolated from 20 failing human heart and from frozen ZL and ZDF rat hearts. The method for RNA extrac-
MATERIALS AND METHODS
Patients
We studied 27 (18 male and 9 female) consecutive patients with NYHA class IV non-ischemic heart failure who were referred to
the Texas Heart Institute and to the DeBakey Heart Center for cardiac transplantation. The mean patient age was 59 years (range:
26–68 years). The mean ejection fraction was 19% (range: 10–28%). Comorbidities were diabetes mellitus type 2 (10 patients)
and obesity (BMI 30; 6 patients). Tissue from the left ventricular free wall was obtained at the time of cardiac transplantation,
frozen in liquid nitrogen, and stored in – 80°C. Hearts of the nonfailing group were obtained from donors not suitable for
transplantation (n 8).
Animals
We obtained male Zucker lean (ZL) and Zucker diabetic fatty (ZDF) rats (age 8 wk, n 6 in each group from Harlan (Indianapolis,
IN, USA) subsequently kept in the Animal Care Center at the University of Texas Medical School at Houston under controlled
conditions (23 1°C; 12 h light/12 h dark cycle), receiving standard laboratory food and water ad libitum. Animals were killed
between 700 and 900 am, the hearts were removed, and a transverse section was made and frozen for histology. The remaining
heart tissue was freeze- clamped for gene expression studies.
Heart perfusions
A separate group of rats was used for isolated working rat heart experiments (n 6). The working heart preparation was described
earlier (12). Hearts were perfused in the working mode with Krebs-Henseleit buffer containing 5 mmol/L d-glucose and sodium
oleate (0.4 mmol/L ) bound to 1% BSA (Cohn fraction V, fatty acid free: Intergen Co., Purchase, NY, respectively. USA).
Preload Cardiac and power afterload was were determined 15 and 100 as cm described of H2O,
previously (13).
Histology
Oil red O staining was performed on heart sections by the Department of Cardiac Pathology at the Texas Heart Institute using
standard procedures. Photomicrographs of ( 10) stained sections were taken on a Zeiss Axiophot microscope
Figure 1. a) R epresentative photomicrographs of low, inter- mediate, and high intramyocardial lipid accumulation. b) Of the 27
failing hearts, 8 exhibited high intramyocardial lipid accumulation (30%), 12 demonstrated moderate staining (44%), and 7 had
low staining (26%). c) I ntramyocardial lipid accumulation was significantly higher in diabetic failing hearts (HF DM) (*P 0.05).
There was a trend for increased intramyocardial lipid deposition in heart failure patients with obesity (HF O) (n.s., P 0.07) d)
Representative photomi- crograph of intramyocardial lipid deposition in the Zucker lean (ZL) (n 6 ) and Zucker diabetic fatty
(ZDF) (n 6) rat heart. e) There is a dramatic increase ( 50-fold) in intramyocardial lipid accumulation in the ZDF rat (*P
0.00001). f) Cardiac power is decreased in the ZDF rat heart compared with lean controls (*P 0 .01).
LIPID OVERLOAD IN THE FAILING HUMAN HEART
1693
tion and for quantitative RT-PCR has been described (14); nucleotideFailing hearts with high intramyocardial lipid
sequences for primers and probes have been published (15, 16). Theaccumulation (HF L), have increased expression of MCAD
transcript for the constitutive gene 18S was used as a housekeepingand mCPT1 (n 6, #P 0.05), but no change in PPAR
gene for data normalization for human studies and -actin was used forranscript levels. b) Intramyocardial lipid staining
rat experiments. Internal standards were prepared using the T7 RNAorrelates with MCAD and mCPT1, but not with PPAR
polymer- ase method (Ambion, Austin, TX, USA). ranscript levels. c) Although MCAD and mCPT1
xpression appear to be higher in heart failure patients with
Statistical analysis obesity (HF O) (n 5 ), values do not reach statistical
ignificance. In heart failure patients with diabetes (HF D)
Data are expressed as mean se. Differences between the groups weren 5 ), there is a significant increase in mCPT1 expression
calculated by a Student t test. Correlations between transcript levels#P 0 .05)
and area intensity of oil red O staining were presented using theintramyocardial lipid accumulation compared with the ZL
Pearson product moment. A value of P 0 .05 was consideredcontrols (Fig. 1d, e).
significant. Because all human subjects had severe end-stage heart
failure, differences in contractile function between groups
could not be assessed. However, in the ZDF rat cardiac power
RESULTS was significantly depressed compared with lean controls (Fig.
1f ).
Intramyocardial lipid accumulation
Of the 27 patients with non-ischemic heart failure, 8 patients

exhibited high lipid deposition, 12 hearts demonstratedWe measured the transcript levels of several key metabolic
moderate oil red O staining, and 7 patients had low levels (Fig.regulators. Medium chain acyl-CoA dehydrogenase (MCAD)
1b) . Therefore, nearly 30% of non-ischemic failing hearts hadand muscle carnitine palmitoyl trans- ferase 1 (mCPT1) are
high intramyocardial lipid deposition. There was a trend forPPAR -regulated genes (5) that regulate fatty acid oxidation in
higher intramyocardial lipid staining among obese patients (Pthe mitochondria. As previously reported (5, 17), there was a
0.07) and significantly higher triglyceride staining in patientssignificant down-regulation of PPAR , MCAD, and mCPT1 in
with diabetes (Fig. 1c). All ZDF rats exhibited severe failing hearts compared with nonfailing hearts (Fig. 2a). When
we analyzed transcript levels in failing hearts with high
intramyocardial lipid accumulation (HF L), we found a
significant increase in PPAR -regulated gene expression (e.g.,
MCAD and mCPT1) (Fig. 2a) . Intramyocardial lipid staining
correlated positively with both MCAD and mCPT1 expression
(Fig. 2b) .
Because we found that intramyocardial triglyceride
accumulation was predominately seen among diabetic and/or
ompared with nonfailing hearts (NF) (n 8),
Figure 2. a) C obese heart failure patients (Fig. 1c) , we sepa- rately analyzed
there is a decrease in PPAR , MCAD, and mCPT1 gene expression in these subgroups. There was a statistically
transcript levels in failing hearts (HF) (n 1 4, *P 0 .01). significant increase in mCPT1
1694 Vol. 18 November 2004 SHARMA ET AL. The FASEB Journal
Metabolic gene expression
expression in diabetic subjects and a trend for an increase inpredominately MHC- isoform has a decreased ATPase activity
mCPT1 transcript levels in obese subjects (Fig. 2c) . Althoughn comparison to MHC- , resulting in decreased contractile
MCAD expression was increased in obese and diabetic failingvelocity but greater economy in force generation (18).
hearts, the values never reached statistical significance. In failing hearts there was a down-regulation of both
In the lipotoxic ZDF rat heart, we observed a signif- MHC- and MHC- expression compared with nonfailing hearts
icant increase in MCAD and mCPT1 transcript levels (Fig. 3a). Fig. 4a) . When failing hearts where sepa- rated into those with
In the human as well as the rodent model, PPAR transcript and without high intramyocardial
levels remained the same, indicating a dissociation between
mRNA expression and PPAR activity.
Sarcomeric genes
To determine whether the accumulation of lipid within the

myocardium is associated with alterations of genes encoding for
contractile protein, we measured the expression of MHC- and
MHC- . Myosin heavy chain, the main component of myosin,
exists in two distinct isoforms (18). Myosin composed of
4b). MHC- expression was increased in failing hearts with
diabetes, while MHC- transcript levels did not change (Fig. 4c) .
There was a trend toward higher MHC- in subjects with obesity
and heart failure. In ZDF rat hearts there was a similar increase
in MHC- transcript levels and no change in MHC- expression
(Fig. 3b) .
TNF- expression
Animal models of lipotoxicity and insulin resistance

demonstrate increased TNF- expression in adipose tissue and
skeletal muscle (8, 9). An increase in cardiac TNF- expression,
Figure 3. a) Although PPAR transcript levels are not
which occurs in heart failure, can induce pathologic remodeling
different between ZDF rat heart and lean controls, MCAD
of the heart character-
and mCPT1 ized is by
expression contractile
increased dysfunction,
(*P 0 .05). b) M HC-
apoptosis, expression
and progres- sive chamber dilation (10, 19, 20).
is up- regulated in the ZDF rat heart (*P 0 .01) As
expected, there was an increase in TNF- transcript levels
whereas MHC- transcript levels are do not change. c) TNF- in
failing hearts compared with nonfailing hearts ( Fig. 5
transcript levels are not different between ZDF rat heartsa , b
) . In
failing hearts withcontrols.
and lean high intramyocardial lipid accumulation
lipid accumulation, there was an increase in MHC- transcript (HF L), there was a marked up-regulation of TNF- expression
levels in lipid-overloaded hearts (Fig. 4a) . There was no (Fig. 5a) . There was a dramatic increase in TNF- transcript
significant change in MHC- expression. MHC- transcript levelslevels in the diabetic and obese failing hearts (Fig. 5b) . In
correlated positively with intramyocardial lipid staining (Fig. contrast, TNF- tran-
1695 LIPID OVERLOAD IN THE FAILING HUMAN HEART
Figure 4. a) MHC- and MHC- expression is downregulated

in the failing heart. In HF L (n 6 ), MHC- expression was
significantly increased without a change in MHC- . b) MHC-
expression correlates with intramyocardial lipid deposition. c)
In HF O patients (n 5 ), MHC- and MHC- transcript levels do
not change significantly. In failing hearts with diabetes (n 5), cript levels were not different between ZDF and ZL rat hearts
MHC- expression was increased (*P 0 .05). Fig. 3c) .
DISCUSSION
The two main findings of our study are 1) Intramyocar- dial
lipid overload is a relatively common finding in non-ischemic SHARMA ET AL.
heart failure, especially in obese and diabetic patients; 2)
Intramyocardial lipid overload in the failing human heart is
associated with a distinct gene expression profile that is similar
to an animal model of lipotoxicity and cardiac dysfunction.
Triglyceride accumulation in the failing heart
Under normal physiologic conditions, the heart utilizes fatty

acids as its chief energy substrate (21). Because there is limited
capacity for triglyceride storage in the cardiomyocyte, the
uptake and oxidation of fatty acids is tightly coupled (21).
Accumulation of intramyocardial triglyceride can occur either
because of an increase in fatty acid uptake or an impairment of
fatty acid oxidation. For example, cardiac-specific
overexpression of acyl-CoA synthetase in mice results in
marked increase in fatty acid import resulting in
intramyocardial lipid overload and cardiomyopathy (22). We
have shown that impaired fatty acid oxidation in the obese
Zucker rat contributes to intramyocardial triglyceride
accumulation and contractile dysfunction (3). Here, we found
that 30% of non-ischemic heart failure patients exhibited high
Figure 5. a) In HF (n 1 4), the expression of TNF- is increased (*P
intramyocardial lipid deposition associated with diabetes and
0.05). In HF L (n 6), there is increased TNF- transcript levels (#P
obesity. Because there is impaired fatty acid oxidation in heart
0.05). b) I n HF O and HF D (n 5 each), there is an up-regulation of
failure (17) along with high circulating fatty acid levels in
TNF- expression (#P 0 .05 and $, P 0 .01 compared with HF).
diabetes and/or obesity, we propose that both defects are
Under normal conditions, long chain fatty acids, the natural
responsible for intramyocardial lipid overload (Fig. 6).
ligands for PPAR , induce the expression of PPAR -regulated
In human and in animal studies, intracellular lipidgenes (e.g., MCAD and mCPT1), which in turn increase fatty
accumulation in skeletal muscle and liver is a hallmark ofacid oxidation (5). There- fore, delivery and the oxidation of
insulin resistance (23–25). Lipid overload in non- adiposefatty acids are tightly coupled. For example, during fasting or
tissues may increase the production of reactive oxygenafter a high-fat meal, increased delivery of fatty acids to the
intermediates, ceramide, and/or activate signaling pathwaysheart activates PPAR , which increases fatty acid oxidation
(e.g., PKC ) implicated in conveying insulin resistance inappropriately. We found that PPAR -regulated gene expression
skeletal muscle and liver (23–25). As in skeletal muscle andwas up-regulated in hearts with intramyocardial lipid overload,
liver, metabolic dysregulation in lipid overloaded hearts mayindicating that high intracellular fatty acid levels are activating
induce insulin resistance. Because failing hearts alreadyPPAR . Yet despite severe intramyocardial lipid accumulation,
exhibit impaired fatty acid oxidation (17), superimposedPPAR -regulated genes were up-regulated only up to the level
myocardial insulin resistance may impair glucose oxidationof nonfailing hearts, suggesting a mismatch between fatty acid
resulting in “energy starvation” of the heart. delivery and oxidation. Down-regulation of PPAR transcript
Heart failure itself is associated with significant met-levels in the failing heart may limit the capacity of long chain
abolic abnormalities. Heart failure causes systemic in- sulinfatty acids to activate PPAR , suggesting impairment in fatty
resistance (26). Moreover, Nikolaidis et al. demonstrated thatacid oxidative capacity. We have shown a similar impairment in
pacing-induced dilated cardiomyopathy in dogs inducesfatty acid oxidation in the obese Zucker rat (3). Thus, we
myocardial insulin resistance (27). Although we observed apropose that the combination of increased fatty acid delivery to
slight increase in triglyceride
1696 Vol. 18 November 2004 The FASEB Journal

Figure 6. Both increased fatty acid delivery (e.g., diabetes, obesity, etc) and impaired fatty acid oxidation (e.g., heart failure) result in severe
intramyocardial triglyceride accumulation. The dysregulation of fatty acid metabolism in the lipid-overloaded failing hearts is associated with
increased expression of PPAR -regulated genes, MHC- and TNF- . All three changes in gene expression can induce cardiac dysfunction.
1697 LIPID OVERLOAD IN THE FAILING HUMAN HEART

deposition in failing human hearts, we found significant
accumulation of intramyocardial lipid only in heart failure
patients with diabetes and/or obesity indicating that impaired
fatty acid oxidation alone (e.g., heart failure) does not result in
the accumulation of intramyocardial triglycerides.
Metabolic dysregulation in the lipid overloaded

failing heart
(32). the myocardium, along with impaired fatty acid oxida-
Others have shown that PPAR coactivator 1 tion in heart failure, results in the severe accumulation
(PGC-1), a potent activator of PPAR , regulates MEF-2 of intramyocardial lipid (Fig. 6).
transcriptional activity(33). We have previously demonstrated that PPAR reactivation in pressure overload
hypertrophy results in
TNF- expression in the lipid overloaded contractile dysfunction (7). Genetically engineered
failing heart mice overexpressing PPAR in the heart develop contractile dysfunction when exposed to high serum
fatty acid levels (6). Therefore, we speculate that increased PPAR activity in the lipid overloaded failing heart
actually contributes to contractile dysfunction.
Because long chain fatty acids are natural ligands for PPAR , increased delivery of fatty acids would result in an
increase in PPAR activity and not necessarily PPAR expression itself. Therefore, we speculate that the discordance
between PPAR expression and PPAR -regulated gene expression we observed is pri- marily due to activation of
PPAR by long chain fatty acids. Pharmacologic activation of PPAR (e.g., WY- 14,643) results in a similar increase
in MCAD and mCPT1 expression without a change in PPAR expression itself (7) .
Except for an increase in mCPT1 expression, we did not observe a statistically significant difference in other PPAR
-regulated genes in diabetic or obese failing hearts. It is likely that variability in the severity of the underlying
metabolic disorder and drug treatment influences metabolic gene expression in a manner that precludes the ability to
determine statistically significant changes. Because animal models of diabetes and obesity are associated with lipid
accumulation in the heart (2–4), intramyocardial triglyceride accumulation may represent a more accurate marker
for the metabolic perturbations associated with diabetes and obesity.
Heart failure, diabetes, and obesity are recognized as states of chronic inflammation (10, 34). TNF- is an important
cytokine that may play a role in all three of these conditions. In human heart failure, TNF- expression is increased
in the myocardium and correlates with the severity of the disease (10). In animal models, TNF- directly impairs
contractile function, and cardiac overexpression of TNF- induces pathologic remodeling of the heart (19, 20, 35).
In patients with obesity and diabetes, TNF- transcript levels are increased in peripheral tissues and correlate with
insulin resistance (8, 9). TNF- can directly impair insulin signaling in peripheral tissues (34). In fact, insulin
resistance associated with severe heart failure is thought to be mediated by increased serum TNF- levels (10). We
found that TNF- expression was increased in failing hearts with intramyocardial lipid overload, diabetes, and
obesity. Although the mechanism for increased TNF- expression remains to be elucidated, high serum TNF- levels
in severely insulin resistant heart failure patients can activate NF- B signaling pathways, which in turn induce
TNF- expression in the cardiomyocyte in a feed-forward mechanism (10, 34). In short, increased TNF- expression in
the lipid- overloaded myocardium may contribute to insulin resistance, contractile dysfunction, and pathologic re-
modeling in failing hearts with lipid overload
Lipid overloaded failing human heart vs. ZDF Myosin-isogene expression in the lipid-overloaded
rat heart failing heart
The ZDF rat is an extensively studied model of lipotox- In failing hearts with intramyocardial lipid overload or
icity and type II diabetes mellitus caused by a mutation diabetes, MHC- transcript levels were increased
(loss of function) in the leptin receptor (2). After 4 wk whereas MHC- expression did not change. In heart
of age the rats develop obesity, high serum fatty acid failure, there is a differential down-regulation of
levels, skeletal muscle, and heart lipid accumulation MHC- and MHC- resulting in a dramatic decrease in
(2). We examined intramyocardial lipid staining, con- the percentage of myosin composed of MHC- (28).
tractile function, and gene expression in ZDF and ZL This change in myosin content, which results in an
rat hearts at 8 wk of age, when severe insulin resistant increase in MHC- composition, may contribute to
occurs but not -cell failure (L. Golfman et al. unpub- contractile dysfunction. For example, thyroid deple-
lished observations). Therefore, alterations in cardiac tion, cardiomyopathy, and pressure overload hypertro-
gene expression between ZDF and ZL rats likely repre- phy in rodents increase MHC- expression and result
sent lipotoxicity and not insulinopenia. in contractile dysfunction (29). Cardiac-specific overex-
We demonstrate that ZDF rats have high intramyo- pression of MHC- results in decreased systolic func-
cardial lipid accumulation and impaired cardiac power tion (30). Although the mechanism for the increased
in vitro. Although the ZDF rats are clinically not in MHC- expression in the lipid overloaded failing
heart failure, our findings suggest that intramyocardial hearts is unknown, similar changes in myosin iso-gene
lipid overload impairs contractile reserve. Because re- expression occur in rats given high-fat diet or given the
activation of PPAR in pressure overload hypertrophy fatty acid oxidation inhibitor, etomoxir (31). Recently,
worsens contractile function (7), the increase in PPAR we demonstrated that patients with diabetes and heart
activity in the ZDF rat heart, as well as failing human failure had a decrease in MHC- expression, possibly
hearts with lipid overload, may contribute to cardiac regulated by myocyte enhancement factor 2 (MEF-2)
dysfunction. Increased PPAR activity and fatty acid
SHARMA ET AL.
oxidation are associated with an increase in reactive oxygen intermediates known to impair contractile function in
the heart (6). Like the lipid overloaded failing human heart, the ZDF rat heart exhibited increased expression of
MHC- , which can contribute to a decreased contractile function. Because the ZDF rats are not clinically in heart
failure, baseline PPAR transcript levels were different from with ZL controls.
An important observation in the ZDF rat is that their cardiac gene expression profile is nearly the same as the failing
human hearts with lipid overload, indicating that the underlying transcriptional changes associated with excessive
triglyceride deposition are the same for humans and rodents. Because treatment of the ZDF rat with
insulin-sensitizing drugs removes intramyocardial triglyceride deposits and improves contractile function (2, 4), we
propose that similar improvement in the coupling between fatty acid delivery and oxidation in the lipid overloaded
failing heart may improve cardiac function.
The lack of an increase in TNF- transcript levels in the ZDF rat heart was an unexpected finding. We speculate that
increased TNF- expression occurs at a later stage in the ZDF rat, augmenting insulin resistance and diabetes in the
rat model. Unlike the ZDF rat, which is a model of lipotoxicity-induced diabetes, conditions commonly associated
with abnormal lipid accumulation in non-adipose tissues (e.g., diabetes and obesity) are not a monogenic disorder.
Accumulation of lipid in non-adipose tissues is probably just one of a number of cellular abnormalities that lead to
insulin resistance and tissue dysfunction.
CONCLUSIONS
We have identified a subgroup of heart failure patients with severe metabolic dysregulation characterized by
intramyocardial triglyceride accumulation. Further- more, the lipid-overloaded failing human heart is associated
with a transcriptional profile similar to that of an animal model of lipotoxicity and contractile dysfunction,
suggesting that dysregulation of fatty acid metabolism may contribute cardiac dysfunction.
4. Zhou, Y. T., Grayburn, P., Karim, A., Shimabukuro, M., Higa, M., Baetens, D., Orci, L., and Unger, R. H. (2000) Lipotoxic heart disease in
obese rats: implications for human obesity. Proc. Natl. Acad. Sci. USA 9 7, 1784–1789 5. Barger, P. M., and Kelly, D. P. (2000) PPAR signaling
in the control of cardiac energy metabolism. Trends Cardiovasc. Med. 1 0, 238–245 6. Finck, B. N., Han, X., Courtois, M., Aimond, F., Nerbonne,
J., Kovacs, A., Gross, R. W., and Kelly, D. P. (2003) A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic
cardiomyopathy: modulation by dietary fat content. Proc. Natl. Acad. Sci. USA 100, 1226–1231 7. Young, M. E., Laws, F. A., Goodwin, G. W.,
and Taegtmeyer, H. (2001) Reactivation of peroxisome proliferator-activated receptor alpha is associated with contractile dysfunction in
hypertro- phied rat heart. J. Biol. Chem. 2 76, 44390–44395 8. Hotamisligil, G. S., Arner, P., Caro, J. F., Atkinson, R. L., and Spiegelman, B. M.
(1995) Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J. Clin. Invest. 9 5,
2409–2415 9. Kern, P. A., Saghizadeh, M., Ong, J. M., Bosch, R. J., Deem, R., and Simsolo, R. B. (1995) The expression of tumor necrosis factor
in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J. Clin. Invest. 9 5, 2111–2119 10. Mann, D. L.
(2002) Tumor necrosis factor-induced signal transduction and left ventricular remodeling. J. Card. Fail. 8 , S379–S386 11. Listenberger, L. L.,
and Schaffer, J. E. (2002) Mechanisms of lipoapoptosis: implications for human heart disease. Trends Cardiovasc. Med. 1 2, 134–138 12.
Taegtmeyer, H., Hems, R., and Krebs, H. A. (1980) Utilization of energy providing substrates in the isolated working rat heart. Biochem. J. 1 86,
701–711 13. Goodwin, G. W., Taylor, C. S., and Taegtmeyer, H. (1998) Regulation of energy metabolism of the heart during acute increase in
heart work. J. Biol. Chem. 273, 29530–29539 14. Depre, C., Shipley, G. L., Chen, W., Han, Q., Doenst, T., Moore, M. L., Stepkowski, S., Davies,
P. J. A., and Taegtmeyer, H. (1998) Unloaded heart in vivo replicates fetal gene expression of cardiac hypertrophy. Nat. Med. 4 , 1269–1275 15.
Razeghi, P., Young, M. E., Alcorn, J. L., Moravec, C. S., Frazier, O. H., and Taegtmeyer, H. (2001) Metabolic gene expression in fetal and
failing human heart. Circulation 1 04, 2923–2931 16. Razeghi, P., Sharma, S., Ying, J., Li, Y. P., Stepkowski, S., Reid, M. B., and Taegtmeyer, H.
(2003) Atrophic remodeling of the heart in vivo simultaneously activates pathways of protein syn- thesis and degradation. Circulation 108,
2536–2541 17. Sack, M. N., Rader, T. A., Park, S., Bastin, J., McCune, S. A., and Kelly, D. P. (1996) Fatty acid oxidation enzyme gene
expression is downregulated in the failing heart. Circulation 9 4, 2837–2842 18. Holubarsch, C., Goulette, R. P., Litten, R. Z., Martin, B. J.,
Mulieri, L. A., and Alpert, N. R. (1985) The economy of isometric force development, myosin isoenzyme pattern and myofibrillar ATPase
activity in normal and hypothyroid rat myocardium. Circ. Res. 56, 78–86
This study was supported in part by grants from the NHLBI (RO1-HL073162-01, RO1-HL/AG 61483, and T32-HL 07591 to
H.T.). We would like to acknowledge Stacy Vigil for
19. Kubota, T., McTiernan, C. F., Frye, C. S., Slawson, S. E., Lemster, B. H., Koretsky, A. P., Demetris, A. J., and Feldman, A. M. (1997)
Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ. Res. 81, editorial
assistance.
627–635 20. Sivasubramanian, N., Coker, M. L., Kurrelmeyer, K. M., MacLel- lan, W. R., DeMayo, F. J., Spinale, F. G., and Mann, D. L. (2001)
Left ventricular remodeling in transgenic mice with cardiac R EFERENCES
restricted overexpression of tumor necrosis factor. Circulation 1 04, 826–831 1. Kelly, D. P., Hale, D. E., Rutledge, S. L., Ogden, M. L., Whelan,
A. J., Zhang, Z., and Strauss, A. W. (1992) Molecular basis of inherited medium-chain acyl-CoA dehydrogenase deficiency causing sudden child
death. J. Inherit. Metab. Dis. 15, 171–180 2. Unger, R. H. (2003) The physiology of cellular liporegulation.
Annu. Rev. Physiol. 6 5, 333–347 3. Young, M. E., Guthrie, P. H., Razeghi, P., Leighton, B., Abbasi,
21. Taegtmeyer, H. (1994) Energy metabolism of the heart: from basic concepts to clinical applications. Curr. Prob. Cardiol. 19, 57–116 22.
Chiu, H. C., Kovacs, A., Ford, D. A., Hsu, F. F., Garcia, R., Herrero, P., Saffitz, J. E., and Schaffer, J. E. (2001) A novel mouse model of
lipotoxic cardiomyopathy. J. Clin. Invest. 1 07, 813–822 S., Patil, S., and Taegtmeyer, H. (2002) Impaired long chain
23. Cooney, G. J., Thompson, A. L., Furler, S. M., Ye, J., and fatty acid oxidation and contractile dysfunction in the obese
Kraegen, E. W. (2002) Muscle long-chain acyl CoA esters and Zucker rat heart. Diabetes 51, 2587–2595
insulin resistance. Ann. N.Y. Acad. Sci. 967, 196–207
LIPID OVERLOAD IN THE FAILING HUMAN HEART
1699
31. 24. Boden, G. (2004) Fatty acids and insulin resistance. In Diabetes
Rupp, H., Schulze, W., and Vetter, R. (1995) Dietary medium- Mellitus: A Fundamental and Clinical Text (LeRoith, D., Taylor,
chain triglycerides can prevent changes in myosin and SR due S. I., and Olefsky, J. M., eds) pp. 979–986, Lippincott Williams
to CPT-1 inhibition by etomoxir. Am. J. Physiol. 269, R630– and Wilkins, New York
R640 25. Stein, D. T. (2004) Triglyceride in muscle. In Diabetes Mellitus: A
32. Razeghi, P., Young, M. E., Cockrill, T. C., Frazier, O. H., and Fundamental and Clinical Text ( LeRoith, D., Taylor, S. I., and
Taegtmeyer, H. (2002) Downregulation of myocardial myocyte Olefsky, J. M., eds) pp. 987–1002, Lippincott Williams and
enhancer factor 2C and myocyte enhancer factor 2C-regulated Wilkins, New York
gene expression in diabetic patients with non-ischemic heart 26. Paolisso, G., De Riu, S., Marrazzo, G., Verza, M., Varricchio, M.,
failure. Circulation 106, 407–411 and D'Onofrio, F. (1991) Insulin resistance and hyperinsulin-
33. Czubryt, M. P., McNally, J., Fishman, G. I., and Olson, E. N. emia in patients with chronic congestive heart failure. Metabo-
(2003) Regulation of peroxisome proliferator-activated recep- lism 40, 972–977
tor gamma coactivator 1 alpha (PGC-1 alpha) and mitochon- 27. Nikolaidis, L. A., Sturzu, A., Stolarski, C., Elahi, D., Shen, Y. T.,
drial function by MEF2 and HDAC5. Proc. Natl. Acad. Sci. USA a nd Shannon, R. P. (2004) The development of myocardial
100, 1711–1716 insulin resistance in conscious dogs with advanced dilated
34. Hotamisligil, G. S. (2004) Inflammation, tumor necrosis cardiomyopathy. Cardiovasc. Res. 61, 297–306
factor alpha, and insulin resistance. In Diabetes Mellitus: A 2 8. Miyata, S., Minobe, W., Bristow, M., and Leinwand, L. (2000)
Fundamental and Clinical Text ( LeRoith, D., Taylor, S. I., and Myosin heavy chain isoform expression in the failing and
Olefsky, J. M., eds) pp. 953–962, Lippincott Williams and nonfailing human heart. Circ. Res. 86, 386–390
Wilkins, New York 29. Swynghedauw, B. (1986) Developmental and functional adap-
35. Suffredini, A. F., Fromm, R. E., Parker, M. M., Brenner, M., tation of contractile proteins in cardiac and skeletal muscles.
Kovacs, J. A., Wesley, R. A., and Parrillo, J. E. (1989) The Physiol. Rev. 66, 710–771
cardiovascular response of normal humans to the administra- 30. Tardiff, J. C., Hewett, T. E., Factor, S. M., Vikstrom, K. L.,
tion of endotoxin. N. Engl. J. Med. 321, 1828–1830 Robbins, J., and Leinwand, L. A. (2000) Expression of the beta (slow)-isoform of MHC in
the adult mouse heart causes domi-
Received for publication May 13, 2004. n ant-negative functional effects. Am. J. Physiol. 278, H412–H419
Accepted for publication July 14, 2004.
SHARMA ET AL.

Sharma, S. Et Al. Intramyocardial Lipid Accumulation in The Failing Human Heart Resembles The Lipotoxic Rat Heart. FASEB J. 18, 1692-1700

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Sharma, S. Et Al. Intramyocardial Lipid Accumulation in The Failing Human Heart Resembles The Lipotoxic Rat Heart. FASEB J. 18, 1692-1700

Uploaded by

Copyright:

Available Formats

See discussions, stats, and author profiles for this publication at: