Left ventricular diastolic function in type 2 diabetes mellitus is associated with myocardial triglyceride content but not with impaired myocardial perfusion reserve

Korosoglou, Grigorios; Humpert, Per M.; Ahrens, Johannes; Oikonomou, Dimitrios; Osman, Nael F.; Gitsioudis, Gitsios; Buss, Sebastian J.; Steen, Henning; Schnackenburg, B; Bierhaus, Angelika; Nawroth, Peter P.; Katus, Hugo A.

doi:10.1002/jmri.22879

Cited by 75 publications

(64 citation statements)

References 60 publications

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“…25 Overall, 26,27 Likewise, a significant association between myocardial steatosis and impaired diastolic function has been shown by perfusion MR in T2DM. 5,6 In this study, intramyocardial triglyceride was not a determinant of diastolic function in multivariable analyses, including hepatic triglyceride and VAT. Similarly, neither epi-nor pericardial fat depots correlated with the 2 parameters reflecting best the LV diastolic function.…”

Section: Discussionmentioning

confidence: 53%

“…4 Proton magnetic resonance spectroscopy ( 1 H-MRS) has revealed that triglyceride increase also in cardiomyocytes can be a marker of cardiac function. 5,6 Early subclinical left ventricular (LV) diastolic dysfunction, as measured by tissue Doppler echocardiography, has been shown to associate with NAFLD in nondiabetic 7 and in T2DM 8 subjects. To date, few MRS studies have been published on cardiac function in NAFLD, and the results are controversial.…”

Section: See Editorial By Sarma Et Al See Clinical Perspectivementioning

confidence: 99%

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Ectopic Fat Depots and Left Ventricular Function in Nondiabetic Men With Nonalcoholic Fatty Liver Disease

Granér

Nyman

Sirén

et al. 2015

Circ: Cardiovascular Imaging

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Background-Nonalcoholic fatty liver disease has emerged as a novel cardiovascular risk factor. The aim of the study was to assess the effect of different ectopic fat depots on left ventricular (LV) function in subjects with nonalcoholic fatty liver disease. Methods and Results-Myocardial and hepatic triglyceride contents were measured with 1.5 T magnetic resonance spectroscopy and LV function, visceral adipose tissue (VAT) and subcutaneous adipose tissue, epicardial and pericardial fat by MRI in 75 nondiabetic men. Subjects were stratified by hepatic triglyceride content into low, moderate, and high liver fat groups. Myocardial triglyceride, epicardial and pericardial fat, VAT, and subcutaneous adipose tissue increased stepwise from low to high liver fat group. Parameters of LV diastolic function showed a stepwise decrease over tertiles of liver fat and VAT, and they were inversely correlated with hepatic triglyceride, VAT, and VAT/subcutaneous adipose tissue ratio. In multivariable analyses, hepatic triglyceride and VAT were independent predictors of LV diastolic function, whereas myocardial triglyceride was not associated with measures of diastolic function. Conclusions-Myocardial triglyceride, epicardial and pericardial fat increased with increasing amount of liver fat and VAT. Hepatic steatosis and VAT associated with significant changes in LV structure and function. The association of LV diastolic function with hepatic triglyceride and VAT may be because of toxic systemic effects. The effects of myocardial triglyceride on LV structure and function seem to be more complex than previously thought and merit further study. (Circ Cardiovasc Imaging. 2015;8:e001979.

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Section: Discussionmentioning

confidence: 53%

Section: See Editorial By Sarma Et Al See Clinical Perspectivementioning

confidence: 99%

Ectopic Fat Depots and Left Ventricular Function in Nondiabetic Men With Nonalcoholic Fatty Liver Disease

Granér

Nyman

Sirén

et al. 2015

Circ: Cardiovascular Imaging

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“…Multiple studies have demonstrated an increase in myocardial FAO and triglyceride content in humans with diabetes and metabolic syndrome (98)(99)(100). In some studies, myocardial steatosis has been shown to be an independent predictor of pathologic remodeling and cardiac dysfunction (101)(102)(103). Interestingly, the increased lipid accumulation is associated with higher myocardial FAO rates in diabetic patients, at least in the early stages of disease (104,105).…”

Section: Control Of Cardiac Mitochondrial Biogenesis and Dynamics: Thmentioning

confidence: 99%

Cardiac nuclear receptors: architects of mitochondrial structure and function

Vega¹,

Kelly²

2017

Journal of Clinical Investigation

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The adult mammalian heart has immense energy demands in order to support its role as a constantly active pump. Indeed, the human heart generates and utilizes kilogram quantities of ATP each day. The vast majority of ATP produced in the cardiac myocyte is generated via oxidative phosphorylation (OXPHOS) within a very-high-capacity mitochondrial system. The heart must continually adapt to changing physiologic conditions that influence workload, as well as alterations in oxygen and energy substrate availability. Notably, given that the heart has a limited capacity for fuel storage, it must utilize several energy substrates in an efficient and dynamic manner. As will be described, members of the nuclear receptor transcription factor superfamily serve to dynamically control preference and capacity for cardiac mitochondrial fuel metabolism during development and in response to myriad physiologic conditions. In addition, alterations in nuclear receptor signaling occur with pathologic cardiac growth and remodeling en route to heart failure.The adult cardiac myocyte has a higher density of mitochondria than any other cell type (1). The biogenesis of this highcapacity mitochondrial system occurs largely during the perinatal stage of development. This process involves a major burst of mitochondrial biogenesis at birth, followed by a period of mitochondrial maturation and remodeling during the postnatal period (2). Recent evidence indicates that postnatal mitochondrial maturation involves highly coordinated events including mitophagy, biogenesis, and dynamics (fusion and fission), resulting in a mitochondria network that is densely packed between sarcomeres to directly supply ATP to support cardiac contraction (2). The adult cardiac mitochondria are equipped with enzymatic machinery capable of oxidizing multiple substrates including fatty acids (the chief fuel) as well as glucose (pyruvate) and ketone bodies. This mitochondrial developmental maturation process occurs in parallel with well-characterized changes in the expression of contractile apparatus isoforms, ion channels, and calcium handling proteins. The collective perinatal programming in energy metabolic and structural genes results in an efficient and enduring pump for the adult life of the organism.The postnatal heart has an amazing capacity to oxidize multiple fuels and, therefore, is "omnivorous." Pioneering work by multiple groups has defined dynamic shifts in fuel utilization capacity and preferences during development and in disease states. The fetal and immediate postnatal heart relies primarily on glucose (glycolysis) and lactate as energy sources (3-5). However, very soon after birth the heart shifts to fatty acids as the major fuel substrate, coincident with the mitochondrial biogenic response (Figure 1 and refs. 5-8). The level of glucose oxidation also increases (8). The postnatal heart is also capable of oxidizing ketones, albeit at a low level, concomitant with the postnatal rise in circulating ketones (5). The shifts in fuel preference after birth ar...

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“…Several studies have pointed to the role of lipotoxicity in diabetic cardiomyopathy [2][3][4][5][6][7]. Furthermore, several studies have shown a correlation between the degree of lipid accumulation and cardiac dysfunction in human diabetic hearts [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Lipotoxic Palmitate Impairs the Rate of β-Oxidation and Citric Acid Cycle Flux in Rat Neonatal Cardiomyocytes

Haffar

Akoumi²,

Bousette³

2016

Cell Physiol Biochem

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Background/Aims: Diabetic hearts exhibit intracellular lipid accumulation. This suggests that the degree of fatty acid oxidation (FAO) in these hearts is insufficient to handle the elevated lipid uptake. We previously showed that palmitate impaired the rate of FAO in primary rat neonatal cardiomyocytes. Here we were interested in characterizing the site of FAO impairment induced by palmitate since it may shed light on the metabolic dysfunction that leads to lipid accumulation in diabetic hearts. Methods: We measured fatty acid oxidation, acetyl-CoA oxidation, and carnitine palmitoyl transferase (Cpt1b) activity. We measured both forward and reverse aconitase activity, as well as NAD+ dependent isocitrate dehydrogenase activity. We also measured reactive oxygen species using the 2', 7'-Dichlorofluorescin Diacetate (DCFDA) assay. Finally we used thin layer chromatography to assess diacylglycerol (DAG) levels. Results: We found that palmitate significantly impaired mitochondrial β-oxidation as well as citric acid cycle flux, but not Cpt1b activity. Palmitate negatively affected net aconitase activity and isocitrate dehydrogenase activity. The impaired enzyme activities were not due to oxidative stress but may be due to DAG mediated PKC activation. Conclusion: This work demonstrates that palmitate, a highly abundant fatty acid in human diets, causes impaired β-oxidation and citric acid cycle flux in primary neonatal cardiomyocytes. This metabolic defect occurs prior to cell death suggesting that it is a cause, rather than a consequence of palmitate mediated lipotoxicity. This impaired mitochondrial metabolism can have important implications for metabolic diseases such as diabetes and obesity.

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Left ventricular diastolic function in type 2 diabetes mellitus is associated with myocardial triglyceride content but not with impaired myocardial perfusion reserve

Cited by 75 publications

References 60 publications

Ectopic Fat Depots and Left Ventricular Function in Nondiabetic Men With Nonalcoholic Fatty Liver Disease

Ectopic Fat Depots and Left Ventricular Function in Nondiabetic Men With Nonalcoholic Fatty Liver Disease

Cardiac nuclear receptors: architects of mitochondrial structure and function

Lipotoxic Palmitate Impairs the Rate of β-Oxidation and Citric Acid Cycle Flux in Rat Neonatal Cardiomyocytes

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