Rutger W. van der Meer

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.

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.

Prolonged caloric restriction in obese patients with type 2 diabetes mellitus decreases myocardial triglyceride content and improves myocardial function.

OBJECTIVES This study sought to assess the effects of prolonged caloric restriction in obese patients with type 2 diabetes mellitus (T2DM) on myocardial triglyceride (TG) content and myocardial function. BACKGROUND Myocardial TG content is increased in patients with T2DM and may reflect altered myocardial function. It is unknown whether myocardial TG content is influenced during a therapeutic intervention. METHODS Myocardial TG content (magnetic resonance [MR] spectroscopy), myocardial function (MR imaging), plasma hemoglobin A1c, and body mass index (BMI) were measured in 12 obese, insulin-treated T2DM patients before and after a 16-week very-low-calorie diet (VLCD) (450 kcal/day) to achieve substantial weight loss. Insulin was stopped during the VLCD. RESULTS The BMI decreased from 35.6 +/- 1.2 kg/m(2) (baseline, mean +/- SEM) to 27.5 +/- 1.3 kg/m(2) (after the VLCD, p < 0.001) and was associated with an improvement in hemoglobin A1c from 7.9 +/- 0.4% (baseline) to 6.3 +/- 0.3% (after the VLCD, p = 0.006). Myocardial TG content decreased from 0.88 +/- 0.12% to 0.64 +/- 0.14%, respectively (p = 0.019), and was associated with improved diastolic function (reflected by the ratio between the early and atrial filling phase) from 1.02 +/- 0.08 to 1.18 +/- 0.06, respectively (p = 0.019). CONCLUSIONS Prolonged caloric restriction in obese T2DM patients decreases BMI and improves glucoregulation associated with decreased myocardial TG content and improved diastolic heart function. Therefore, myocardial TG stores in obese patients with T2DM are flexible and amendable to therapeutic intervention by caloric restriction.

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.

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 [18F]-2-fluoro-2-deoxy-d-glucose and [11C]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.

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 A1c >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.

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 1H-magnetic resonance spectroscopy (MRS) to determine myocardial and hepatic triglyceride content, 31P-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 ∼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 ∼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/s2 × 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.

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 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-low<or=5.56% vs. T2DM-high>5.56%). 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 (Pearsons 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.

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.