| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,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
1Correspondence: Department of Internal Medicine, Division of Cardiology, University of Texas Houston-Medical School, 6431 Fannin, MSB 1.246, Houston, TX 77030, USA. E-mail: Heinrich.Taegtmeyer{at}uth.tmc.edu
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
(PPAR) -regulated genes, myosin heavy chain ß (MHC-ß), and tumor necrosis factor (TNF-). Intramyocardial lipid overload in the hearts of ZDF rats was associated with contractile dysfunction and changes in gene expression similar to changes found in failing human hearts with lipid overload. Our findings identify a subgroup of patients with heart failure and severe metabolic dysregulation characterized by intramyocardial triglyceride overload and changes in gene expression that are associated with contractile dysfunction.—Sharma, S., Adrogue, J. V., Golfman, L., Uray, I., Lemm, J., Youker, K., Noon, G. P., Frazier, O. H., Taegtmeyer, H. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart.
Key Words: triglyceride accumulation • contractile dysfunction • non-ischemic heart failure • lipotoxicity
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
, 2)
. In animal models of obesity and diabetes, triglyceride accumulation within cardiomyocytes is associated with impaired contractile function (2
3
4)
. Treatment with insulin-sensitizing drugs not only reduces the deposition of lipid in the myocardium but reverses contractile dysfunction in lipotoxic rats, suggesting that intramyocardial triglyceride accumulation is deleterious (4)
.
Although it is unclear how lipids induce cardiac dysfunction, accumulation of intramyocardial triglyceride is associated with altered gene expression (2)
. Specifically, there is increased expression of the peroxisome proliferator-activated receptor (PPAR) -regulated genes (2
3
4)
. PPAR is a nuclear receptor that, when activated by long chain fatty acids, induces the expression of proteins that increase the uptake and oxidation of fatty acids (5)
. Cardiac-specific overexpression of PPAR induces cardiac dysfunction in mice exposed to high circulating fatty acid levels (6)
. Pharmacologic activation of PPAR in the pressure-overloaded rat heart contributes to contractile dysfunction (7)
. In patients with 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)
. TNF- can directly cause contractile dysfunction in the heart and has been implicated in pathologic remodeling in heart failure (10)
. The accumulation of excess lipid within cardiomyocytes may lead to the production of toxic lipid intermediates, which can induce cell death (2
, 4
, 11)
. Collectively, the term cardiac lipotoxicity refers to this constellation of altered fatty acid 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 triglyceride 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 failure and diabetes and/or obesity exhibited significant intramyocardial lipid deposition associated with a gene expression profile similar to that of the ZDF rat heart.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
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, USA). Preload and afterload were 15 and 100 cm of H2O, respectively. Cardiac power was determined as described 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 (x10) stained sections were taken on a Zeiss Axiophot microscope using 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 was defined as 0.61 to 1.00 AU. High lipid deposition was defined as >1.00 AU. Figure 1
a shows representative photomicrographs of low, moderate, and high intramyocardial lipid deposits.
|
Candidate genes
RNA was isolated from 20 failing human heart and from frozen ZL and ZDF rat hearts. The method for RNA extraction and for quantitative RT-PCR has been described (14)
; nucleotide sequences for primers and probes have been published (15
, 16)
. The transcript for the constitutive gene 18S was used as a housekeeping gene for data normalization for human studies and ß-actin was used for rat experiments. Internal standards were prepared using the T7 RNA polymerase method (Ambion, Austin, TX, USA).
Statistical analysis
Data are expressed as mean ±SE. Differences between the groups were calculated by a Student t test. Correlations between transcript levels and area intensity of oil red O staining were presented using the Pearson product moment. A value of P <0.05 was considered significant.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
). Therefore, nearly 30% of non-ischemic failing hearts had high intramyocardial lipid deposition. There was a trend for higher intramyocardial lipid staining among obese patients (P=0.07) and significantly higher triglyceride staining in patients with diabetes (Fig. 1c
). All ZDF rats exhibited severe intramyocardial lipid accumulation compared with the ZL controls (Fig. 1d, e
).
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 was significantly depressed compared with lean controls (Fig. 1f
).
Metabolic gene expression
We measured the transcript levels of several key metabolic regulators. Medium chain acyl-CoA dehydrogenase (MCAD) and muscle carnitine palmitoyl transferase 1 (mCPT1) are PPAR-regulated genes (5)
that regulate fatty acid oxidation in the mitochondria. As previously reported (5
, 17)
, there was a significant down-regulation of PPAR, MCAD, and mCPT1 in failing hearts compared with nonfailing hearts (Fig. 2
a). 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 obese heart failure patients (Fig. 1c
), we separately analyzed gene expression in these subgroups. There was a statistically significant increase in mCPT1 expression in diabetic subjects and a trend for an increase in mCPT1 transcript levels in obese subjects (Fig. 2c
). Although MCAD expression was increased in obese and diabetic failing hearts, the values never reached statistical significance.
In the lipotoxic ZDF rat heart, we observed a significant increase in MCAD and mCPT1 transcript levels (Fig. 3
a). In the human as well as the rodent model, PPAR transcript 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-ß. Myosin heavy chain, the main component of myosin, exists in two distinct isoforms (18)
. Myosin composed of predominately MHC-ß isoform has a decreased ATPase activity in comparison to MHC-, resulting in decreased contractile velocity but greater economy in force generation (18)
.
In failing hearts there was a down-regulation of both MHC-ß and MHC- expression compared with nonfailing hearts (Fig. 4
a). When failing hearts where separated into those with and without high intramyocardial lipid accumulation, there was an increase in MHC-ß transcript levels in lipid-overloaded hearts (Fig. 4a
). There was no significant change in MHC- expression. MHC-ß transcript levels correlated positively with intramyocardial lipid staining (Fig. 4b
). MHC-ß expression was increased in failing hearts with diabetes, while MHC- transcript levels did not change (Fig. 4c
). There was a trend toward higher MHC-ß in subjects with obesity and heart failure. In ZDF rat hearts there was a similar increase in MHC-ß 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, which occurs in heart failure, can induce pathologic remodeling of the heart characterized by contractile dysfunction, apoptosis, and progressive chamber dilation (10
, 19
, 20)
. As expected, there was an increase in TNF- transcript levels in failing hearts compared with nonfailing hearts (Fig. 5
a, b). In failing hearts with high intramyocardial lipid accumulation (HF+L), there was a marked up-regulation of TNF- expression (Fig. 5a
). There was a dramatic increase in TNF- transcript levels in the diabetic and obese failing hearts (Fig. 5b
). In contrast, TNF- transcript levels were not different between ZDF and ZL rat hearts (Fig. 3c
).
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
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 intramyocardial lipid deposition associated with diabetes and obesity. Because there is impaired fatty acid oxidation in heart failure (17)
along with high circulating fatty acid levels in diabetes and/or obesity, we propose that both defects are responsible for intramyocardial lipid overload (Fig. 6
).
|
In human and in animal studies, intracellular lipid accumulation in skeletal muscle and liver is a hallmark of insulin resistance (23
24
25)
. Lipid overload in non-adipose tissues may increase the production of reactive oxygen intermediates, ceramide, and/or activate signaling pathways (e.g., PKC 
) implicated in conveying insulin resistance in skeletal muscle and liver (23
24
25)
. As in skeletal muscle and liver, metabolic dysregulation in lipid overloaded hearts may induce insulin resistance. Because failing hearts already exhibit impaired fatty acid oxidation (17)
, superimposed myocardial insulin resistance may impair glucose oxidation resulting in "energy starvation" of the heart.
Heart failure itself is associated with significant metabolic abnormalities. Heart failure causes systemic insulin resistance (26)
. Moreover, Nikolaidis et al. demonstrated that pacing-induced dilated cardiomyopathy in dogs induces myocardial insulin resistance (27)
. Although we observed a slight increase in triglyceride 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
Under normal conditions, long chain fatty acids, the natural ligands for PPAR, induce the expression of PPAR-regulated genes (e.g., MCAD and mCPT1), which in turn increase fatty acid oxidation (5)
. Therefore, delivery and the oxidation of fatty acids are tightly coupled. For example, during fasting or after a high-fat meal, increased delivery of fatty acids to the heart activates PPAR, which increases fatty acid oxidation appropriately. We found that PPAR-regulated gene expression was up-regulated in hearts with intramyocardial lipid overload, indicating that high intracellular fatty acid levels are activating PPAR. Yet despite severe intramyocardial lipid accumulation, PPAR-regulated genes were up-regulated only up to the level of nonfailing hearts, suggesting a mismatch between fatty acid delivery and oxidation. Down-regulation of PPAR transcript levels in the failing heart may limit the capacity of long chain fatty acids to activate PPAR, suggesting impairment in fatty acid oxidative capacity. We have shown a similar impairment in fatty acid oxidation in the obese Zucker rat (3)
. Thus, we propose that the combination of increased fatty acid delivery to the myocardium, along with impaired fatty acid oxidation in heart failure, results in the severe accumulation of intramyocardial lipid (Fig. 6)
.
We have previously demonstrated that PPAR reactivation in pressure overload hypertrophy results in contractile dysfunction (7)
. Genetically engineered 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 primarily 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
3
4)
, intramyocardial triglyceride accumulation may represent a more accurate marker for the metabolic perturbations associated with diabetes and obesity.
Myosin-isogene expression in the lipid-overloaded failing heart
In failing hearts with intramyocardial lipid overload or diabetes, MHC-ß transcript levels were increased whereas MHC- expression did not change. In heart failure, there is a differential down-regulation of MHC- and MHC-ß resulting in a dramatic decrease in the percentage of myosin composed of MHC- (28)
. This change in myosin content, which results in an increase in MHC-ß composition, may contribute to contractile dysfunction. For example, thyroid depletion, cardiomyopathy, and pressure overload hypertrophy in rodents increase MHC-ß expression and result in contractile dysfunction (29)
. Cardiac-specific overexpression of MHC-ß results in decreased systolic function (30)
. Although the mechanism for the increased MHC-ß expression in the lipid overloaded failing hearts is unknown, similar changes in myosin iso-gene expression occur in rats given high-fat diet or given the fatty acid oxidation inhibitor, etomoxir (31)
. Recently, we demonstrated that patients with diabetes and heart failure had a decrease in MHC- expression, possibly regulated by myocyte enhancement factor 2 (MEF-2) (32)
. Others have shown that PPAR
coactivator 1 (PGC-1), a potent activator of PPAR, regulates MEF-2 transcriptional activity(33)
.
TNF- expression in the lipid overloaded failing heart
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 remodeling in failing hearts with lipid overload
Lipid overloaded failing human heart vs. ZDF rat heart
The ZDF rat is an extensively studied model of lipotoxicity and type II diabetes mellitus caused by a mutation (loss of function) in the leptin receptor (2)
. After 4 wk of age the rats develop obesity, high serum fatty acid levels, skeletal muscle, and heart lipid accumulation (2)
. We examined intramyocardial lipid staining, contractile function, and gene expression in ZDF and ZL rat hearts at 8 wk of age, when severe insulin resistant occurs but not ß-cell failure (L. Golfman et al. unpublished observations). Therefore, alterations in cardiac gene expression between ZDF and ZL rats likely represent lipotoxicity and not insulinopenia.
We demonstrate that ZDF rats have high intramyocardial lipid accumulation and impaired cardiac power in vitro. Although the ZDF rats are clinically not in heart failure, our findings suggest that intramyocardial lipid overload impairs contractile reserve. Because reactivation of PPAR in pressure overload hypertrophy worsens contractile function (7)
, the increase in PPAR activity in the ZDF rat heart, as well as failing human hearts with lipid overload, may contribute to cardiac dysfunction. Increased PPAR activity and fatty acid 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-ß, 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 |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
|
ACKNOWLEDGMENTS |
|---|
Received for publication May 13, 2004. Accepted for publication July 14, 2004.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  R. Harmancey, C. R. Wilson, and H. Taegtmeyer Adaptation and Maladaptation of the Heart in Obesity Hypertension, August 1, 2008; 52(2): 181 - 187. [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Chess and W. C. Stanley Role of diet and fuel overabundance in the development and progression of heart failure Cardiovasc Res, July 15, 2008; 79(2): 269 - 278. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Tominaga, H. Katoh, K. Odagiri, Y. Takeuchi, H. Kawashima, M. Saotome, T. Urushida, H. Satoh, and H. Hayashi Different effects of palmitoyl-L-carnitine and palmitoyl-CoA on mitochondrial function in rat ventricular myocytes Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H105 - H112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. L. Holland and S. A. Summers Sphingolipids, Insulin Resistance, and Metabolic Disease: New Insights from in Vivo Manipulation of Sphingolipid Metabolism Endocr. Rev., June 1, 2008; 29(4): 381 - 402. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Lei, S. Mason, D. Liu, Y. Huang, C. Marks, R. Hickey, I. S. Jovin, M. Pypaert, R. S. Johnson, and F. J. Giordano Hypoxia-Inducible Factor-Dependent Degeneration, Failure, and Malignant Transformation of the Heart in the Absence of the von Hippel-Lindau Protein Mol. Cell. Biol., June 1, 2008; 28(11): 3790 - 3803. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. D. Abel, S. E. Litwin, and G. Sweeney Cardiac Remodeling in Obesity Physiol Rev, April 1, 2008; 88(2): 389 - 419. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hammer, R. W. van der Meer, H. J. Lamb, M. Schar, A. de Roos, J. W. A. Smit, and J. A. Romijn Progressive Caloric Restriction Induces Dose-Dependent Changes in Myocardial Triglyceride Content and Diastolic Function in Healthy Men J. Clin. Endocrinol. Metab., February 1, 2008; 93(2): 497 - 503. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. W. van der Meer, S. Hammer, J. W.A. Smit, M. Frolich, J. J. Bax, M. Diamant, L. J. Rijzewijk, A. de Roos, J. A. Romijn, and H. J. Lamb Short-Term Caloric Restriction Induces Accumulation of Myocardial Triglycerides and Decreases Left Ventricular Diastolic Function in Healthy Subjects Diabetes, December 1, 2007; 56(12): 2849 - 2853. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. S. Szczepaniak, R. G. Victor, L. Orci, and R. H. Unger Forgotten but Not Gone: The Rediscovery of Fatty Heart, the Most Common Unrecognized Disease in America Circ. Res., October 12, 2007; 101(8): 759 - 767. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. W. van der Meer, J. Doornbos, S. Kozerke, M. Schar, J. J. Bax, S. Hammer, MSc, J. W. A. Smit, J. A. Romijn, M. Diamant, L. J. Rijzewijk, et al. Metabolic Imaging of Myocardial Triglyceride Content: Reproducibility of 1H MR Spectroscopy with Respiratory Navigator Gating in Volunteers Radiology, October 1, 2007; 245(1): 251 - 257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. L. Ruberg Myocardial Lipid Accumulation in the Diabetic Heart Circulation, September 4, 2007; 116(10): 1110 - 1112. [Full Text] [PDF]
|
|
|
|
|
|
J. M. McGavock, I. Lingvay, I. Zib, T. Tillery, N. Salas, R. Unger, B. D. Levine, P. Raskin, R. G. Victor, and L. S. Szczepaniak Cardiac Steatosis in Diabetes Mellitus: A 1H-Magnetic Resonance Spectroscopy Study Circulation, September 4, 2007; 116(10): 1170 - 1175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Glenn and D. G. Gardner Lipids and the Heart: Neither Feast nor Famine Hypertension, September 1, 2007; 50(3): 463 - 464. [Full Text] [PDF]
|
|
|
|
|
|
G. D. Lopaschuk, C. D.L. Folmes, and W. C. Stanley Cardiac Energy Metabolism in Obesity Circ. Res., August 17, 2007; 101(4): 335 - 347. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Boudina and E. D. Abel Diabetic Cardiomyopathy Revisited Circulation, June 26, 2007; 115(25): 3213 - 3223. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Perseghin, G. Ntali, F. De Cobelli, G. Lattuada, A. Esposito, E. Belloni, T. Canu, F. Costantino, F. Ragogna, P. Scifo, et al. Abnormal Left Ventricular Energy Metabolism in Obese Men With Preserved Systolic and Diastolic Functions Is Associated With Insulin Resistance Diabetes Care, June 1, 2007; 30(6): 1520 - 1526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Nisoli, E. Clementi, M. O. Carruba, and S. Moncada Defective Mitochondrial Biogenesis: A Hallmark of the High Cardiovascular Risk in the Metabolic Syndrome? Circ. Res., March 30, 2007; 100(6): 795 - 806. [Abstract] [Full Text] [PDF]
|
|
|
|
 < |
