Activin A is associated with impaired myocardial glucose metabolism and left ventricular remodeling in patients with uncomplicated type 2 diabetes.

BACKGROUND: Activin A released from epicardial adipose tissue has been linked to contractile dysfunction and insulin resistance in cardiomyocytes. This study investigated the role of activin A in clinical diabetic cardiomyopathy by assessing whether circulating activin A levels associate with cardiometabolic parameters in men with uncomplicated type 2 diabetes (T2D), and the effects of treatment with pioglitazone versus metformin on these associations. METHODS: Seventy-eight men with uncomplicated T2D and fourteen healthy men with comparable age were included, in this randomized, double-blind, active comparator intervention study. All T2D men were on glimipiride monotherapy, and randomized to a 24-week intervention with either pioglitazone or metformin. Cardiac dimensions and -function were measured using magnetic resonance imaging, whilst myocardial glucose metabolism (MMRglu) was determined using [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography during a hyperinsulinemic-euglycemic clamp. RESULTS: Circulating activin A levels were comparable in T2D men and controls. Activin A levels were independently inversely associated with MMRglu, and positively with left ventricular mass/volume (LVMV)-ratio in T2D men. Intervention with metformin decreased activin A levels, whereas pioglitazone did not alter activin A levels. The changes in plasma activin A levels were not correlated with the changes in MMRglu following either pioglitazone or metformin treatment. A borderline significant correlation (p = 0.051) of changes in plasma activin A levels and changes in LVMV-ratio was observed after pioglitazone treatment. CONCLUSIONS: Circulating activin A levels are associated with impaired myocardial glucose metabolism and high LVMV-ratio in patients with uncomplicated T2D, reflecting a potential detrimental role in early human diabetic cardiomyopathy. TRIAL REGISTRATION NUMBER: Current Controlled Trials SRCTN53177482.

Myocardial steatosis and biventricular strain and strain rate imaging in patients with type 2 diabetes mellitus.

BACKGROUND: Magnetic resonance spectroscopy can quantify myocardial triglyceride content in type 2 diabetic patients. Its relation to alterations in left (LV) and right (RV) ventricular myocardial functions is unknown. METHODS AND RESULTS: A total of 42 men with type 2 diabetes mellitus were recruited. Exclusion criteria included hemoglobin A(1c) >8.5, known cardiovascular disease, diabetes-related complications, or blood pressure >150/85 mm Hg. Myocardial ischemia was excluded by a negative dobutamine stress test. LV and RV volumes and ejection fraction were quantified by magnetic resonance imaging. LV global longitudinal and RV free wall longitudinal strain, systolic strain rate, and diastolic strain rate were quantified by echocardiographic speckle tracking analyses. Myocardial triglyceride content was quantified by magnetic resonance spectroscopy and dichotomized on the basis of the median value of 0.76. The median age was 59 years (25th and 75th percentiles, 54 and 62 years). Median diabetes diagnosis duration was 4 years, and median glycohemoglobin level was 6.2 (25th and 75th percentiles, 5.9 and 6.8). There were no differences in LV and RV end-diastolic and end-systolic volume indexes and ejection fraction between patients with high (≥0.76) and those with low (<0.76) myocardial triglyceride content. However, patients with high myocardial triglyceride content had greater impairment of LV and RV myocardial strain and strain rate. The myocardial triglyceride content was an independent correlate of LV and RV longitudinal strain, systolic strain rate, and diastolic strain rate. CONCLUSIONS: High myocardial triglyceride content is associated with more pronounced impairment of LV and RV functions in men with uncomplicated type 2 diabetes mellitus.

Association of plasma osteoprotegerin and adiponectin with arterial function, cardiac function and metabolism in asymptomatic type 2 diabetic men.

BACKGROUND: Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily, is linked to cardiovascular disease. Negative associations exist between circulating OPG and cardiac function. The adipocytokine adiponectin (ADPN) is downregulated in type 2 diabetes mellitus (T2DM) and coronary artery disease and shows an inverse correlation with insulin sensitivity and cardiovascular disease risk. We assessed the relationship of plasma OPG and ADPN and arterial function, cardiac function and myocardial glucose metabolism in T2DM. METHODS: We included 78 asymptomatic men with uncomplicated, well-controlled T2DM, without inducible ischemia, assessed by dobutamine-stress echocardiography, and 14 age-matched controls. Cardiac function was measured by magnetic resonance imaging, myocardial glucose metabolism (MMRglu) by 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography. OPG and ADPN levels were measured in plasma. RESULTS: T2DM patients vs. controls showed lower aortic distensibility, left ventricular (LV) volumes, impaired LV diastolic function and MMRglu (all P < 0.05). In T2DM men vs. controls, OPG levels were higher (P = 0.02), whereas ADPN concentrations were decreased (P = 0.04). OPG correlated inversely with aortic distensibility, LV volumes and E/A ratio (diastolic function), and positively with LV mass/volume ratio (all P < 0.05). Regression analyses showed the associations with aortic distensibility and LV mass/volume ratio to be independent of age-, blood pressure- and glycated hemoglobin (HbA1c). However, the associations with LV volumes and E/A ratio were dependent of these parameters. ADPN correlated positively with MMRglu (P < 0.05), which, in multiple regression analysis, was dependent of whole-body insulin sensitivity, HbA1c and waist. CONCLUSIONS: OPG was inversely associated with aortic distensibility, LV volumes and LV diastolic function, while ADPN was positively associated with MMRglu. These findings indicate that in asymptomatic men with uncomplicated T2DM, OPG and ADPN may be markers of underlying mechanisms linking the diabetic state to cardiac abnormalities. TRIAL REGISTRATION: Current Controlled Trials ISRCTN53177482.

Pioglitazone improves cardiac function and alters myocardial substrate metabolism without affecting cardiac triglyceride accumulation and high-energy phosphate metabolism in patients with well-controlled type 2 diabetes mellitus.

BACKGROUND: Cardiac disease is the leading cause of mortality in type 2 diabetes mellitus (T2DM). Pioglitazone has been associated with improved cardiac outcome but also with an elevated risk of heart failure. We determined the effects of pioglitazone on myocardial function in relation to cardiac high-energy phosphate, glucose, and fatty acid metabolism and triglyceride content in T2DM patients. METHODS AND RESULTS: Seventy-eight T2DM men without structural heart disease or inducible ischemia as assessed by dobutamine stress echocardiography were assigned to pioglitazone (30 mg/d) or metformin (2000 mg/d) and matching placebo for 24 weeks. The primary end point was change in cardiac diastolic function from baseline relative to myocardial metabolic changes, measured by magnetic resonance imaging, proton and phosphorus magnetic resonance spectroscopy, and [(18)F]-2-fluoro-2-deoxy-D-glucose and [(11)C]palmitate positron emission tomography. No patient developed heart failure. Both therapies similarly improved glycemic control, whole-body insulin sensitivity, and blood pressure. Pioglitazone versus metformin improved the early peak flow rate (P=0.047) and left ventricular compliance. Pioglitazone versus metformin increased myocardial glucose uptake (P<0.001), but pioglitazone-related diastolic improvement was not associated with changes in myocardial substrate metabolism. Metformin did not affect myocardial function but decreased cardiac work relative to pioglitazone (P=0.006), a change that was paralleled by a reduced myocardial glucose uptake and fatty acid oxidation. Neither treatment affected cardiac high-energy phosphate metabolism or triglyceride content. Only pioglitazone reduced hepatic triglyceride content (P<0.001). CONCLUSIONS: In T2DM patients, pioglitazone was associated with improvement in some measures of left ventricular diastolic function, myocardial glucose uptake, and whole-body insulin sensitivity. The functional changes, however, were not associated with myocardial substrate and high-energy phosphate metabolism.

Kinetic models for analysing myocardial [(11)C]palmitate data.

PURPOSE: [(11)C]Palmitate PET can be used to study myocardial fatty acid metabolism in vivo. Several models have been applied to describe and quantify its kinetics, but to date no systematic analysis has been performed to define the most suitable model. METHODS: In this study a total of 21 plasma input models comprising one to three compartments and up to six free rate constants were compared using statistical analysis of clinical data and simulations. To this end, 14 healthy volunteers were scanned using [(11)C]palmitate, whilst myocardial blood flow was measured using H(2)(15)O. RESULTS: Models including an oxidative pathway, representing production of (11)CO(2), provided significantly better fits to the data than other models. Model robustness was increased by fixing efflux of (11)CO(2) to the oxidation rate. Simulations showed that a three-tissue compartment model describing oxidation and esterification was feasible when no more than three free rate constants were included. CONCLUSION: Although further studies in patients are required to substantiate this choice, based on the accuracy of data description, the number of free parameters and generality, the three-tissue model with three free rate constants was the model of choice for describing [(11)C]palmitate kinetics in terms of oxidation and fatty acid accumulation in the cell.

The ageing male heart: myocardial triglyceride content as independent predictor of diastolic function.

AIMS: In animal models of obesity and diabetes mellitus, myocardial TG accumulation is associated with decreased myocardial function. In the physiologically ageing heart, myocardial triglyceride (TG) accumulation may also occur due to reduced myocardial fatty acid oxidation. The role of myocardial TG in the ageing human heart is unknown. Therefore, the purpose of our study was to evaluate the effects of ageing on myocardial TG content, and to determine the association between myocardial TG content and heart function. METHODS AND RESULTS: 1H-magnetic resonance spectroscopy and magnetic resonance imaging of the heart were performed in 43 healthy male subjects. Mean age (range) of the subjects was 44 (20-66) years. Body mass index (BMI), blood pressure, and biochemical markers were determined. Age correlated significantly to myocardial TG content (r = 0.57, P < 0.05) independently of BMI. Furthermore, myocardial TG content correlated negatively with left ventricular diastolic function (represented by E/A ratio, r = -0.68, P < 0.05). Multivariable analysis indicated myocardial TG content as independent predictor (P < 0.05) of the age related decrease in diastolic heart function. CONCLUSION: Myocardial TG content increases in the physiologically ageing male heart and is associated with the age-related decline in diastolic function, independent of BMI, blood pressure, and biochemical blood markers.

Effects of short-term high-fat, high-energy diet on hepatic and myocardial triglyceride content in healthy men.

CONTEXT: An association has been suggested between elevated plasma nonesterified fatty acid (NEFA) levels, myocardial triglyceride (TG) accumulation, and myocardial function. OBJECTIVE: Our objective was to investigate the effects of an elevation of plasma NEFA by a high-fat, high-energy (HFHE) diet on hepatic and myocardial TG accumulation, and on myocardial function. DESIGN: There were 15 healthy males (mean +/- sd age: 25.0 +/- 6.6 yr) subjected to a 3-d HFHE diet consisting of their regular diet, supplemented with 800 ml cream (280 g fat) every day. METHODS: (1)H-magnetic resonance spectroscopy was performed for assessing hepatic and myocardial TGs. Furthermore, left ventricular function was assessed using magnetic resonance imaging. RESULTS: The HFHE diet increased hepatic TGs compared with baseline (from 2.01 +/- 1.79 to 4.26 +/- 2.78%; P = 0.001) in parallel to plasma TGs and NEFA. Myocardial TGs did not change (0.38 +/- 0.18 vs. 0.40 +/- 0.12%; P = 0.7). The HFHE diet did not change myocardial systolic function. Diastolic function, assessed by dividing the maximum flow across the mitral valve of the early diastolic filling phase by the maximum flow of the atrial contraction (E/A ratio), decreased compared with baseline (from 2.11 +/- 0.39 to 1.89 +/- 0.33; P = 0.031). This difference was no longer significant after adjustment for heart rate (P = 0.12). CONCLUSIONS: Short-term HFHE diet in healthy males results in major increases in plasma TG and NEFA concentrations and hepatic TGs, whereas it does not influence myocardial TGs or myocardial function. These observations indicate differential, tissue-specific partitioning of TGs and/or fatty acids among nonadipose organs during HFHE diet.

Stroke volume measurements with first-pass dynamic positron emission tomography: comparison with cardiovascular magnetic resonance.

BACKGROUND: The assessment of forward stroke volume (SV) using dynamic, first-pass cardiac positron emission tomography (PET) was shown to be feasible in a limited number of studies with small numbers of subjects. The aim of this study was to compare first-pass derived SV with cardiovascular magnetic resonance imaging (CMR)-obtained values in a larger population of subjects. METHODS AND RESULTS: Fifty-nine subjects with varying degrees of cardiac function were studied. Stroke volume was assessed using oxygen-15-labeled water (H(2)(15)O) dynamic first-pass PET for both the right ventricle (RV) and left ventricle (LV), and compared with the findings of aorta velocity-encoded phase-contrast CMR. The PET-estimated SV was higher for the RV than for the LV (133 +/- 34 vs 116 +/- 31 mL, P < .01, +/- SD), and both were higher compared with values obtained by CMR (81 +/- 20 mL, both P < .01, +/- SD). Although significant, the correlations between PET and CMR were moderate for both the RV (r = 0.37, P < .01) and the LV (r = 0.40, P < .01, +/- SD). Bland-Altman analysis revealed a progressive overestimation with increasing SV measured in either ventricle. CONCLUSIONS: First-pass dynamic H(2)(15)O PET for the assessment of forward SV is feasible, although values are progressively overestimated with increasing SV, particularly when the RV is used, and correlations with aorta velocity-encoded phase-contrast CMR are moderate. These findings are probably protocol-dependent and warrant further study before the use of first-pass dynamic H(2)(15)O PET in clinical or research settings can be advocated.

Right ventricular involvement in diabetic cardiomyopathy.

OBJECTIVE: To compare magnetic resonance imaging-derived right ventricular (RV) dimensions and function between men with type 2 diabetes and healthy subjects, and to relate these parameters to left ventricular (LV) dimensions and function. RESEARCH DESIGN AND METHODS: RV and LV volumes and functions were assessed in 78 men with uncomplicated type 2 diabetes and 28 healthy men within the same range of age using magnetic resonance imaging. Steady-state free precession sequences were used to assess ventricular dimensions. Flow velocity mapping across the pulmonary valve and tricuspid valve was used to assess RV outflow and diastolic filling patterns, respectively. Univariate general linear models were used for statistical analyses. RESULTS: RV end-diastolic volume was significantly decreased in patients compared with healthy subjects after adjustment for BMI and pulse pressure (177 ± 28 mL vs. 197 ± 47 mL, P < 0.01). RV systolic function was impaired: peak ejection rate across the pulmonary valve was decreased (433 ± 54 mL/s vs. 463 ± 71 mL/s, P < 0.01) and pulmonary flow acceleration time was longer (124 ± 17 ms vs. 115 ± 25 ms, P < 0.05). Indexes of RV diastolic function were impaired: peak filling rate and peak deceleration gradient of the early filling phase were 315 ± 63 mL/s vs. 356 ± 90 mL/s (P < 0.01) and 2.3 ± 0.8 mL/s(2) × 10(-3) vs. 2.8 ± 0.8 mL/s(2) × 10(-3) (P < 0.01), respectively. All RV parameters were strongly associated with its corresponding LV parameter (P < 0.001). CONCLUSIONS: Diabetic cardiomyopathy affects the right ventricle, as demonstrated by RV remodeling and impaired systolic and diastolic functions in men with type 2 diabetes, in a similar manner as changes in LV dimensions and functions. These observations suggest that RV impairment might be a component of the diabetic cardiomyopathy phenotype.

Cardioprotective properties of omentin-1 in type 2 diabetes: evidence from clinical and in vitro studies.

CONTEXT: Adipokines are linked to the development of cardiovascular dysfunction in type 2 diabetes (DM2). In DM2-patients, circulating levels of omentin-1, an adipokine preferentially expressed in epicardial adipose tissue, are decreased. This study investigated whether omentin-1 has a cardioprotective function. METHODS: Omentin-1 levels in plasma and cardiac fat depots were determined in DM2-patients versus controls. Moreover, the relation between omentin-1 levels and cardiac function was examined in men with uncomplicated DM2. Finally, we determined whether omentin-1 could reverse the induction of cardiomyocyte dysfunction by conditioned media derived from epicardial adipose tissue from patients with DM2. RESULTS: Omentin-1 was highly expressed and secreted by epicardial adipose tissue, and reduced in DM2. Circulating omentin-1 levels were lower in DM2 versus controls, and positively correlated with the diastolic parameters early peak filling rate, early deceleration peak and early deceleration mean (all P<0.05). The improved diastolic function following pioglitazone treatment associated with increases in omentin-1 levels (P<0.05). In vitro, exposure of cardiomyocytes to conditioned media derived from epicardial adipose tissue from patients with DM2 induced contractile dysfunction and insulin resistance, which was prevented by the addition of recombinant omentin. CONCLUSION: These data identify omentin-1 as a cardioprotective adipokine, and indicate that decreases in omentin-1 levels could contribute to the induction of cardiovascular dysfunction in DM2.

Liver fat content in type 2 diabetes: relationship with hepatic perfusion and substrate metabolism.

OBJECTIVE: Hepatic steatosis is common in type 2 diabetes. It is causally linked to the features of the metabolic syndrome, liver cirrhosis, and cardiovascular disease. Experimental data have indicated that increased liver fat may impair hepatic perfusion and metabolism. The aim of the current study was to assess hepatic parenchymal perfusion, together with glucose and fatty acid metabolism, in relation to hepatic triglyceride content. RESEARCH DESIGN AND METHODS: Fifty-nine men with well controlled type 2 diabetes and 18 age-matched healthy normoglycemic men were studied using positron emission tomography to assess hepatic tissue perfusion, insulin-stimulated glucose, and fasting fatty acid metabolism, respectively, in relation to hepatic triglyceride content, quantified by proton magnetic resonance spectroscopy. Patients were divided into two groups with hepatic triglyceride content below (type 2 diabetes-low) or above (type 2 diabetes-high) the median of 8.6%. RESULTS: Type 2 diabetes-high patients had the highest BMI and A1C and lowest whole-body insulin sensitivity (ANOVA, all P < 0.001). Compared with control subjects and type 2 diabetes-low patients, type 2 diabetes-high patients had the lowest hepatic parenchymal perfusion (P = 0.004) and insulin-stimulated hepatic glucose uptake (P = 0.013). The observed decrease in hepatic fatty acid influx rate constant, however, only reached borderline significance (P = 0.088). In type 2 diabetic patients, hepatic parenchymal perfusion (r = -0.360, P = 0.007) and hepatic fatty acid influx rate constant (r = -0.407, P = 0.007) correlated inversely with hepatic triglyceride content. In a pooled analysis, hepatic fat correlated with hepatic glucose uptake (r = -0.329, P = 0.004). CONCLUSIONS: In conclusion, type 2 diabetic patients with increased hepatic triglyceride content showed decreased hepatic parenchymal perfusion and hepatic insulin mediated glucose uptake, suggesting a potential modulating effect of hepatic fat on hepatic physiology.

Effects of hepatic triglyceride content on myocardial metabolism in type 2 diabetes.

OBJECTIVES: The purpose of this study was to investigate the relationship between hepatic triglyceride content and both myocardial function and metabolism in type 2 diabetes mellitus (T2DM). BACKGROUND: Heart disease is the leading cause of mortality in T2DM. Central obesity and hepatic steatosis, both hallmark abnormalities in T2DM, have been related to increased risk of heart disease. METHODS: Sixty-one T2DM patients underwent myocardial perfusion and substrate metabolism measurements by positron emission tomography, using [15O]water, [11C]palmitate, and [18F]-2-fluoro-2-deoxy-D-glucose. In addition, whole-body insulin sensitivity (M/I) was determined. Myocardial left ventricular function and high-energy phosphate metabolism were measured using magnetic resonance imaging and [31P]-magnetic resonance spectroscopy, respectively. Hepatic triglyceride content was measured by proton magnetic resonance spectroscopy. Patients were divided according to hepatic triglyceride content (T2DM-low5.56%). RESULTS: In addition to decreased M/I (p=0.002), T2DM-high patients had reduced myocardial perfusion (p=0.001), glucose uptake (p=0.005), and phosphocreatine/adenosine triphosphate (PCr/ATP) ratio (p=0.003), compared with T2DM-low patients, whereas cardiac fatty acid metabolism and left ventricular function were not different. Hepatic triglyceride content correlated inversely with M/I (Pearson's r=-0.620, p<0.001), myocardial glucose uptake (r=-0.413, p=0.001), and PCr/ATP (r=-0.442, p=0.027). Insulin sensitivity correlated positively with myocardial glucose uptake (r=0.528, p<0.001) and borderline with myocardial PCr/ATP (r=0.367, p=0.072), whereas a positive association was found between cardiac glucose uptake and PCr/ATP (r=0.481, p=0.015). CONCLUSIONS: High liver triglyceride content in T2DM was associated with decreased myocardial perfusion, glucose uptake, and high-energy phosphate metabolism in conjunction with impaired M/I. The long-term clinical implications of hepatic steatosis with respect to cardiac metabolism and function in the course of T2DM require further study.

Pioglitazone decreases plasma cholesteryl ester transfer protein mass, associated with a decrease in hepatic triglyceride content, in patients with type 2 diabetes.

OBJECTIVE: Thiazolidinediones reduce hepatic steatosis and increase HDL cholesterol levels. In mice with human-like lipoprotein metabolism (APOE*3-Leiden.CETP transgenic mice), a decrease in hepatic triglyceride content is associated with a decrease in plasma cholesteryl ester transfer protein (CETP) mass and an increase in HDL levels. Therefore, the aim of the present study was to assess the effects of pioglitazone on CETP mass in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We included 78 men with type 2 diabetes (aged 56.5 +/- 0.6 years; HbA1c 7.1 +/- 0.1%) who were randomly assigned to treatment with pioglitazone (30 mg/day) or metformin (2000 mg/day) and matching placebo, in addition to glimepiride. At baseline and after 24 weeks of treatment plasma HDL cholesterol levels and CETP mass were measured, and hepatic triglyceride content was assessed by proton magnetic resonance spectroscopy. RESULTS Pioglitazone decreased hepatic triglyceride content (5.9 [interquartile range 2.6-17.4] versus 4.1 [1.9-12.3]%, P < 0.05), decreased plasma CETP mass (2.33 +/- 0.10 vs. 2.06 +/- 0.10 microg/ml, P < 0.05), and increased plasma HDL cholesterol level (1.22 +/- 0.05 vs. 1.34 +/- 0.05 mmol/l, P < 0.05). Metformin did not significantly change any of these parameters. CONCLUSIONS: A decrease in hepatic triglyceride content by pioglitazone is accompanied by a decrease in plasma CETP mass and associated with an increase in HDL cholesterol levels. These results in patients with type 2 diabetes fully confirm recent findings in mice.

Altered myocardial substrate metabolism and decreased diastolic function in nonischemic human diabetic cardiomyopathy: studies with cardiac positron emission tomography and magnetic resonance imaging.

OBJECTIVES: This study was designed to evaluate myocardial substrate and high-energy phosphate (HEP) metabolism in asymptomatic men with well-controlled, uncomplicated type 2 diabetes with verified absence of cardiac ischemia, and age-matched control subjects, and to assess the association with myocardial function. BACKGROUND: Metabolic abnormalities, particularly an excessive exposure of the heart to circulating nonesterified fatty acids and myocardial insulin resistance are considered important contributors to diabetic cardiomyopathy in animal models of diabetes. The existence of myocardial metabolic derangements in uncomplicated human type 2 diabetes and their possible contribution to myocardial dysfunction still remain undetermined. METHODS: In 78 insulin-naive type 2 diabetes men (age 56.5 +/- 5.6 years, body mass index 28.7 +/- 3.5 kg/m(2), glycosylated hemoglobin A(1c) 7.1 +/- 1.0%; expressed as mean +/- SD) without cardiac ischemia and 24 normoglycemic control subjects (age 54.5 +/- 7.1 years, body mass index 27.0 +/- 2.5 kg/m(2), glycosylated hemoglobin A(1c) 5.3 +/- 0.2%), we assessed myocardial left ventricular (LV) function by magnetic resonance imaging, and myocardial perfusion and substrate metabolism by positron emission tomography using H(2)(15)O, carbon (11)C-palmitate, and 18-fluorodeoxyglucose 2-fluoro-2-deoxy-D-glucose. Cardiac HEP metabolism was assessed by phosphorous P 31 magnetic resonance spectroscopy. RESULTS: In patients, compared with control subjects, LV diastolic function (E/A ratio: 1.04 +/- 0.25 vs. 1.26 +/- 0.36, p = 0.003) and myocardial glucose uptake (260 +/- 128 nmol/ml/min vs. 348 +/- 154 nmol/ml/min, p = 0.015) were decreased, whereas myocardial nonesterified fatty acid uptake (88 +/- 31 nmol/ml/min vs. 68 +/- 18 nmol/ml/min, p = 0.021) and oxidation (85 +/- 30 nmol/ml/min vs. 63 +/- 19 nmol/ml/min, p = 0.007) were increased. There were no differences in myocardial HEP metabolism or perfusion. No association was found between LV diastolic function and cardiac substrate or HEP metabolism. CONCLUSIONS: Patients versus control subjects showed impaired LV diastolic function and altered myocardial substrate metabolism, but unchanged HEP metabolism. We found no direct relation between cardiac diastolic function and parameters of myocardial metabolism.

Findings from left ventricular strain and strain rate imaging in asymptomatic patients with type 2 diabetes mellitus.

Regional left ventricular (LV) myocardial functional changes in early diabetic cardiomyopathy have not been well documented. LV multidirectional strain and strain rate analyses by 2-dimensional speckle tracking were used to detect subtle myocardial dysfunction in 47 asymptomatic, male patients (age 57 +/- 6 years) with type 2 diabetes mellitus. The results were compared to those from 53 male controls matched by age, body mass index, and body surface area. No differences were found in the LV end-diastolic volume index (40.7 +/- 8.9 vs 44.1 +/- 7.8 ml/m(2), p = NS), end-systolic volume index (16.0 +/- 4.8 vs 17.8 +/- 4.3 ml/m(2), p = NS), ejection fraction (61.0 +/- 5.5% vs 59.8 +/- 5.3%, p = NS). The transmitral E/A (0.95 +/- 0.21 vs 1.12 +/- 0.32, p = 0.007) and pulmonary S/D (1.45 +/- 0.28 vs 1.25 +/- 0.27, p = 0.001) ratios were more impaired in the patients with diabetes mellitus. Importantly, the diabetic patients had impaired longitudinal, but preserved circumferential and radial systolic and diastolic, function. Diabetes mellitus was an independent predictor for longitudinal strain, systolic strain rate and early diastolic strain rate on multiple linear regression analysis (all p <0.001). In conclusion, the LV longitudinal systolic and diastolic function were impaired, but the circumferential and radial functions were preserved in patients with uncomplicated type 2 diabetes mellitus.

Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus.

OBJECTIVES: The purpose of this study was to compare myocardial triglyceride content and function between patients with uncomplicated type 2 diabetes mellitus (T2DM) and healthy subjects within the same range of age and body mass index (BMI), and to study the associations between myocardial triglyceride content and function. BACKGROUND: T2DM is a major risk factor for cardiovascular disease. Increasing evidence is emerging that lipid oversupply to cardiomyocytes plays a role in the development of diabetic cardiomyopathy, by causing lipotoxic injury and myocardial steatosis. METHODS: Myocardial triglyceride content and myocardial function were measured in 38 T2DM patients and 28 healthy volunteers in the same range of age and BMI by proton magnetic resonance (MR) spectroscopy and MR imaging, respectively. Myocardial triglyceride content was calculated as a percentage relative to the signal of myocardial water. RESULTS: Myocardial triglyceride content was significantly higher in T2DM patients compared with healthy volunteers (0.96 +/- 0.07% vs. 0.65 +/- 0.05%, p < 0.05). Systolic function did not significantly differ between both groups. Indexes of diastolic function, including the ratio of maximal left ventricular early peak filling rate and the maximal left ventricular atrial peak filling rate (E/A) and E peak deceleration, were significantly impaired in T2DM compared with those in healthy subjects (1.08 +/- 0.04 ml/s(2) x 10(-3) vs. 1.24 +/- 0.06 ml/s(2) x 10(-3) and 3.6 +/- 0.2 ml/s(2) x 10(-3) vs. 4.4 +/- 0.3 ml/s(2) x 10(-3), respectively, p < 0.05). Multivariable analysis indicated that myocardial triglyceride content was associated with E/A and E peak deceleration, independently of diabetic state, age, BMI, heart rate, visceral fat, and diastolic blood pressure. CONCLUSIONS: Myocardial triglyceride content is increased in uncomplicated T2DM and is associated with impaired left ventricular diastolic function, independently of age, BMI, heart rate, visceral fat, and diastolic blood pressure.

Short-term caloric restriction induces accumulation of myocardial triglycerides and decreases left ventricular diastolic function in healthy subjects.

OBJECTIVE: Diabetes and obesity are associated with increased plasma nonesterified fatty acid (NEFA) levels, myocardial triglyceride accumulation, and myocardial dysfunction. Because a very low-calorie diet (VLCD) also increases plasma NEFA levels, we studied the effect of a VLCD on myocardial triglyceride content and cardiac function in healthy subjects. RESEARCH DESIGN AND METHODS: Fourteen healthy nonobese men underwent (1)H-magnetic resonance spectroscopy (MRS) to determine myocardial and hepatic triglyceride content, (31)P-MRS to assess myocardial high-energy phosphate (HEP) metabolism (phosphocreatine/ATP), and magnetic resonance imaging of myocardial function at baseline and after a 3-day VLCD. RESULTS: After the dietary intervention, plasma NEFA levels increased compared with those at baseline (from 0.5 +/- 0.1 to 1.1 +/- 0.1 mmol/l, P < 0.05). Concomitantly, myocardial triglyceride content increased by approximately 55% compared with that at baseline (from 0.38 +/- 0.05 to 0.59 +/- 0.06%, P < 0.05), whereas liver triglyceride content decreased by approximately 32% (from 2.2 +/- 0.5 to 1.5 +/- 0.4%, P < 0.05). The VLCD did not change myocardial phosphocreatine-to-ATP ratio (2.33 +/- 0.15 vs. 2.33 +/- 0.08, P > 0.05) or systolic function. Interestingly, deceleration of the early diastolic flow across the mitral valve decreased after the VLCD (from 3.37 +/- 0.20 to 2.91 +/- 0.16 ml/s(2) x 10(-3), P < 0.05). This decrease in diastolic function was significantly correlated with the increase in myocardial triglyceride content. CONCLUSIONS: Short-term VLCD induces accumulation of myocardial triglycerides. In addition, VLCD decreases left ventricular diastolic function, without alterations in myocardial HEP metabolism. This study documents diet-dependent physiological variations in myocardial triglyceride content and diastolic function in healthy subjects.

Metabolic imaging of myocardial triglyceride content: reproducibility of 1H MR spectroscopy with respiratory navigator gating in volunteers.

Institutional review board approval and informed consent were obtained. The purpose of the study was to prospectively compare spectral resolution and reproducibility of hydrogen 1 (1H) magnetic resonance (MR) spectroscopy, with and without respiratory motion compensation based on navigator echoes, in the assessment of myocardial triglyceride content in the human heart. In 20 volunteers (14 men, six women; mean age+/-standard error, 31 years+/-2.8 [range, 19-60 years]; body mass index, 19-30 kg/m2) without history of cardiovascular disease, 1H MR spectroscopy of the myocardium was performed at rest, with and without respiratory motion compensation. Unsuppressed water signal linewidth changed from 11.9 Hz to 10.7 Hz (P<.001) with the use of the navigator, which indicated better spectral resolution. The navigator improved the intraclass correlation coefficient for the assessment of myocardial triglyceride content from 0.32 to 0.81. Therefore, the authors believe that respiratory motion correction is essential for reproducible assessment of myocardial triglycerides.