Limits...
Altered myocardial substrate metabolism is associated with myocardial dysfunction in early diabetic cardiomyopathy in rats: studies using positron emission tomography.

van den Brom CE, Huisman MC, Vlasblom R, Boontje NM, Duijst S, Lubberink M, Molthoff CF, Lammertsma AA, van der Velden J, Boer C, Ouwens DM, Diamant M - Cardiovasc Diabetol (2009)

Bottom Line: Myocardial functional changes were significantly associated with whole-body insulin sensitivity and decreased myocardial glucose utilisation.ZL hearts a 2.4-fold reduced insulin-mediated phosphorylation of Akt was found (p < 0.05).Using PET and echocardiography, we found increases in myocardial FA oxidation with a concomitant decrease of insulin-mediated myocardial glucose utilisation in early DCM.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Endocrinology, Diabetes Centre, VU University Medical Centre, Amsterdam, The Netherlands. c.vandenbrom@vumc.nl

ABSTRACT

Background: In vitro data suggest that changes in myocardial substrate metabolism may contribute to impaired myocardial function in diabetic cardiomyopathy (DCM). The purpose of the present study was to study in a rat model of early DCM, in vivo changes in myocardial substrate metabolism and their association with myocardial function.

Methods: Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats underwent echocardiography followed by [11C]palmitate positron emission tomography (PET) under fasting, and [18F]-2-fluoro-2-deoxy-D-glucose PET under hyperinsulinaemic euglycaemic clamp conditions. Isolated cardiomyocytes were used to determine isometric force development.

Results: PET data showed a 66% decrease in insulin-mediated myocardial glucose utilisation and a 41% increase in fatty acid (FA) oxidation in ZDF vs. ZL rats (both p < 0.05). Echocardiography showed diastolic and systolic dysfunction in ZDF vs. ZL rats, which was paralleled by a significantly decreased maximal force (68%) and maximal rate of force redevelopment (69%) of single cardiomyocytes. Myocardial functional changes were significantly associated with whole-body insulin sensitivity and decreased myocardial glucose utilisation. ZDF hearts showed a 68% decrease in glucose transporter-4 mRNA expression (p < 0.05), a 22% decrease in glucose transporter-4 protein expression (p = 0.10), unchanged levels of pyruvate dehydrogenase kinase-4 protein expression, a 57% decreased phosphorylation of AMP activated protein kinase alpha1/2 (p < 0.05) and a 2.4-fold increased abundance of the FA transporter CD36 to the sarcolemma (p < 0.01) vs. ZL hearts, which are compatible with changes in substrate metabolism. In ZDF vs. ZL hearts a 2.4-fold reduced insulin-mediated phosphorylation of Akt was found (p < 0.05).

Conclusion: Using PET and echocardiography, we found increases in myocardial FA oxidation with a concomitant decrease of insulin-mediated myocardial glucose utilisation in early DCM. In addition, the latter was associated with impaired myocardial function. These in vivo data expand previous in vitro findings showing that early alterations in myocardial substrate metabolism contribute to myocardial dysfunction.

Show MeSH

Related in: MedlinePlus

In vivo alterations in myocardial substrate metabolism. Myocardial [11C]palmitate time-activity curve, where the rapid decline reflects clearance of palmitate from the myocardium (A). Two-tissue compartment model used for determining myocardial metabolic rate of glucose utilisation (MMRglu) (B). Typical example of a myocardial [11C]palmitate and 18FDG image in a ZL and ZDF rat normalised for standard uptake value (summed images from 30 to 60 min) (C). Myocardial fatty acid (FA) oxidation rate constant measured under fasting conditions (D), and MMRglu measured under hyperinsulinaemic euglycaemic clamp conditions (E) for ZL rats (open bars) and ZDF rats (filled bars). Data are expressed as mean ± SEM, n = 6–11, * p < 0.05 vs. ZL rats.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2722582&req=5

Figure 1: In vivo alterations in myocardial substrate metabolism. Myocardial [11C]palmitate time-activity curve, where the rapid decline reflects clearance of palmitate from the myocardium (A). Two-tissue compartment model used for determining myocardial metabolic rate of glucose utilisation (MMRglu) (B). Typical example of a myocardial [11C]palmitate and 18FDG image in a ZL and ZDF rat normalised for standard uptake value (summed images from 30 to 60 min) (C). Myocardial fatty acid (FA) oxidation rate constant measured under fasting conditions (D), and MMRglu measured under hyperinsulinaemic euglycaemic clamp conditions (E) for ZL rats (open bars) and ZDF rats (filled bars). Data are expressed as mean ± SEM, n = 6–11, * p < 0.05 vs. ZL rats.

Mentions: PET data were reconstructed using a partial volume corrected – ordered subset expectation maximisation (PVC-OSEM) algorithm [16], leading to an expected effective spatial resolution in the images of ~2.0 mm. Reconstructed images consisted of 256 × 256 × 207 voxels, whereby one voxel measures 1.2 mm in each direction. Regions of interest (ROIs) were placed over the LV cavity and the myocardium in three image planes and decay corrected time-activity curves (TACs) were obtained (AMIDE 0.8.22, amide.sourceforge.net). Regions near the liver were avoided to prevent spillover to the heart. Myocardial [11C]palmitate oxidation rate was derived from a biexponential fit to the TAC (Figure 1A), excluding data points measured before the myocardial uptake reached a maximum. The myocardial oxidation rate equals ln(2) times the inverse of the time constant of the fast exponential [17]. Quantification of myocardial 18FDG utilisation was achieved with compartment analysis, based on a two-tissue compartment model (Figure 1B). The input function was derived from a ROI drawn in three consecutive mid-ventricular slices, with 4 voxels per plane as centrally placed in the cavity as possible. A constant factor of 1.6 was used for the activity concentration ratio between whole blood and plasma. The value of Ki, which represents the fractional rate of tracer influx, was obtained using: Ki = K1·k3/(k2+k3), where K1 and k2 are rate constants for forward and reverse capillary transport of 18FDG and k3 refers to the rate of phosphorylation of 18FDG, as illustrated in figure 1B. The myocardial metabolic rate of glucose utilisation (MMRglu) is then given by MMRglu = Ki·Cglu, where Cglu is the BG concentration.


Altered myocardial substrate metabolism is associated with myocardial dysfunction in early diabetic cardiomyopathy in rats: studies using positron emission tomography.

van den Brom CE, Huisman MC, Vlasblom R, Boontje NM, Duijst S, Lubberink M, Molthoff CF, Lammertsma AA, van der Velden J, Boer C, Ouwens DM, Diamant M - Cardiovasc Diabetol (2009)

In vivo alterations in myocardial substrate metabolism. Myocardial [11C]palmitate time-activity curve, where the rapid decline reflects clearance of palmitate from the myocardium (A). Two-tissue compartment model used for determining myocardial metabolic rate of glucose utilisation (MMRglu) (B). Typical example of a myocardial [11C]palmitate and 18FDG image in a ZL and ZDF rat normalised for standard uptake value (summed images from 30 to 60 min) (C). Myocardial fatty acid (FA) oxidation rate constant measured under fasting conditions (D), and MMRglu measured under hyperinsulinaemic euglycaemic clamp conditions (E) for ZL rats (open bars) and ZDF rats (filled bars). Data are expressed as mean ± SEM, n = 6–11, * p < 0.05 vs. ZL rats.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2722582&req=5

Figure 1: In vivo alterations in myocardial substrate metabolism. Myocardial [11C]palmitate time-activity curve, where the rapid decline reflects clearance of palmitate from the myocardium (A). Two-tissue compartment model used for determining myocardial metabolic rate of glucose utilisation (MMRglu) (B). Typical example of a myocardial [11C]palmitate and 18FDG image in a ZL and ZDF rat normalised for standard uptake value (summed images from 30 to 60 min) (C). Myocardial fatty acid (FA) oxidation rate constant measured under fasting conditions (D), and MMRglu measured under hyperinsulinaemic euglycaemic clamp conditions (E) for ZL rats (open bars) and ZDF rats (filled bars). Data are expressed as mean ± SEM, n = 6–11, * p < 0.05 vs. ZL rats.
Mentions: PET data were reconstructed using a partial volume corrected – ordered subset expectation maximisation (PVC-OSEM) algorithm [16], leading to an expected effective spatial resolution in the images of ~2.0 mm. Reconstructed images consisted of 256 × 256 × 207 voxels, whereby one voxel measures 1.2 mm in each direction. Regions of interest (ROIs) were placed over the LV cavity and the myocardium in three image planes and decay corrected time-activity curves (TACs) were obtained (AMIDE 0.8.22, amide.sourceforge.net). Regions near the liver were avoided to prevent spillover to the heart. Myocardial [11C]palmitate oxidation rate was derived from a biexponential fit to the TAC (Figure 1A), excluding data points measured before the myocardial uptake reached a maximum. The myocardial oxidation rate equals ln(2) times the inverse of the time constant of the fast exponential [17]. Quantification of myocardial 18FDG utilisation was achieved with compartment analysis, based on a two-tissue compartment model (Figure 1B). The input function was derived from a ROI drawn in three consecutive mid-ventricular slices, with 4 voxels per plane as centrally placed in the cavity as possible. A constant factor of 1.6 was used for the activity concentration ratio between whole blood and plasma. The value of Ki, which represents the fractional rate of tracer influx, was obtained using: Ki = K1·k3/(k2+k3), where K1 and k2 are rate constants for forward and reverse capillary transport of 18FDG and k3 refers to the rate of phosphorylation of 18FDG, as illustrated in figure 1B. The myocardial metabolic rate of glucose utilisation (MMRglu) is then given by MMRglu = Ki·Cglu, where Cglu is the BG concentration.

Bottom Line: Myocardial functional changes were significantly associated with whole-body insulin sensitivity and decreased myocardial glucose utilisation.ZL hearts a 2.4-fold reduced insulin-mediated phosphorylation of Akt was found (p < 0.05).Using PET and echocardiography, we found increases in myocardial FA oxidation with a concomitant decrease of insulin-mediated myocardial glucose utilisation in early DCM.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Endocrinology, Diabetes Centre, VU University Medical Centre, Amsterdam, The Netherlands. c.vandenbrom@vumc.nl

ABSTRACT

Background: In vitro data suggest that changes in myocardial substrate metabolism may contribute to impaired myocardial function in diabetic cardiomyopathy (DCM). The purpose of the present study was to study in a rat model of early DCM, in vivo changes in myocardial substrate metabolism and their association with myocardial function.

Methods: Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats underwent echocardiography followed by [11C]palmitate positron emission tomography (PET) under fasting, and [18F]-2-fluoro-2-deoxy-D-glucose PET under hyperinsulinaemic euglycaemic clamp conditions. Isolated cardiomyocytes were used to determine isometric force development.

Results: PET data showed a 66% decrease in insulin-mediated myocardial glucose utilisation and a 41% increase in fatty acid (FA) oxidation in ZDF vs. ZL rats (both p < 0.05). Echocardiography showed diastolic and systolic dysfunction in ZDF vs. ZL rats, which was paralleled by a significantly decreased maximal force (68%) and maximal rate of force redevelopment (69%) of single cardiomyocytes. Myocardial functional changes were significantly associated with whole-body insulin sensitivity and decreased myocardial glucose utilisation. ZDF hearts showed a 68% decrease in glucose transporter-4 mRNA expression (p < 0.05), a 22% decrease in glucose transporter-4 protein expression (p = 0.10), unchanged levels of pyruvate dehydrogenase kinase-4 protein expression, a 57% decreased phosphorylation of AMP activated protein kinase alpha1/2 (p < 0.05) and a 2.4-fold increased abundance of the FA transporter CD36 to the sarcolemma (p < 0.01) vs. ZL hearts, which are compatible with changes in substrate metabolism. In ZDF vs. ZL hearts a 2.4-fold reduced insulin-mediated phosphorylation of Akt was found (p < 0.05).

Conclusion: Using PET and echocardiography, we found increases in myocardial FA oxidation with a concomitant decrease of insulin-mediated myocardial glucose utilisation in early DCM. In addition, the latter was associated with impaired myocardial function. These in vivo data expand previous in vitro findings showing that early alterations in myocardial substrate metabolism contribute to myocardial dysfunction.

Show MeSH
Related in: MedlinePlus