Matti Luotolahti

Glucose Uptake in the Chronically Dysfunctional but Viable Myocardium

BACKGROUND The regulation of glucose uptake in the dysfunctional but viable myocardium has not been studied previously in humans. METHODS AND RESULTS Seven patients with an occluded major coronary artery but no previous infarction were studied twice with 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography, once in the fasting state and once during hyperinsulinemic euglycemic clamping. Myocardial blood flow was measured with [(15)O]H2O. The myocardial region beyond an occluded artery that showed stable wall-motion abnormality represented chronically dysfunctional but viable tissue. Six of the patients were later revascularized, and wall-motion recovery was detected in the corresponding regions, which confirmed viability. A slightly reduced myocardial blood flow was detected in the dysfunctional than in the remote myocardial regions (0.81 +/- 0.27 versus 1.02 +/- 0.23 mL x g(-1) x min(-1),P=.036). In the fasting state, glucose uptake was slightly increased in the dysfunctional regions compared with normal myocardium (15 +/- 10 versus 11 +/- 10 micromol/100 g per minute, P=.038). During insulin clamping, a striking increase in glucose uptake by insulin was obtained in both the dysfunctional and the normal regions (72 +/- 22 and 79 +/- 21 micromol/100 g per minute, respectively; P<.001, fasting versus clamping). CONCLUSIONS Contrary to previous suggestions, glucose uptake can be increased strikingly by insulin in chronically dysfunctional but viable myocardium. This demonstrates that insulin control over glucose uptake is preserved in the dysfunctional myocardium and provides a rational basis for metabolic intervention.

Insulin resistance characterizes glucose uptake in skeletal muscle but not in the heart in NIDDM

Summary Skeletal muscle insulin resistance and coronary heart disease (CHD) often precede non-insulin-dependent diabetes mellitus (NIDDM). A recent study showed the myocardium of patients with CHD to be insulin resistant, independent of blood flow. We determined whether myocardial insulin resistance is a feature of NIDDM patients with no CHD. Skeletal muscle and myocardial glucose uptake were determined in 10 patients with NIDDM and 9 age- and weight-matched normal men of similar age and body mass index men using [18F]-2-fluoro-2-deoxy-d-glucose and positron emission tomography under normoglycaemic hyperinsulinaemic conditions. Whole body glucose uptake, as determined by the euglycaemic clamp technique, was significantly lower in the patients with NIDDM (35 ± 3 μmol/kg body weight · min) than the normal subjects (45 ± 3 μmol/kg body weight · min, p < 0.02). Insulin-stimulated femoral muscle glucose uptake was significantly lower in the patients with NIDDM (71 ± 6 μmol/kg muscle · min) than in the normal subjects (96 ± 5 μmol/kg muscle · min, p < 0.01). Whole body glucose uptake was correlated with femoral muscle glucose uptake in the entire group (r = 0.76, p < 0.001), in patients with NIDDM and in normal subjects. Rates of insulin-stimulated myocardial glucose uptake were comparable between the patients with NIDDM (814 ± 76 μmol/kg muscle · min) and the normal subjects (731 ± 63 μmol/kg muscle · min, p > 0.4). Whole body or femoral muscle, and myocardial glucose uptake were not correlated in all subjects, patients with NIDDM or normal subjects. We conclude that insulin resistance of the myocardium is not a feature of uncomplicated NIDDM. [Diabetologia (1998) 41: 555-559]

Exercise training improves biventricular oxidative metabolism and left ventricular efficiency in patients with dilated cardiomyopathy.

OBJECTIVES The aim of this study was to determine the effect of exercise training on myocardial oxidative metabolism and efficiency in patients with idiopathic dilated cardiomyopathy (DCM) and mild heart failure (HF). BACKGROUND Exercise training is known to improve exercise tolerance and quality of life in patients with chronic HF. However, little is known about how exercise training may influence myocardial energetics. METHODS Twenty clinically stable patients with DCM (New York Heart Association classes I through III) were prospectively separated into a training group (five-month training program; n = 9) and a non-trained control group (n = 11). Oxidative metabolism in both the right and left ventricles (RV and LV) was measured using [(11)C]acetate and positron emission tomography. Myocardial work power was measured using echocardiography. Myocardial efficiency for forward work was calculated as myocardial work power per mass/LV oxidative metabolism. RESULTS Significant improvements were noted in exercise capacity (VO(2)) and ejection fraction in the training group, whereas no changes were observed in the non-trained group. Exercise training reduced both RV and LV oxidative metabolism and elicited a significant increase in LV forward work efficiency, although no significant changes were observed in the non-trained group. CONCLUSIONS Exercise training improves exercise tolerance and LV function. This is accompanied by a decrease in biventricular oxidative metabolism and enhanced forward work efficiency. Therefore, exercise training elicits an energetically favorable improvement in myocardial function and exercise tolerance in patients with DCM.

Myocardial Oxygen Consumption Is Unchanged but Efficiency Is Reduced in Patients With Essential Hypertension and Left Ventricular Hypertrophy

BACKGROUND Patients with hypertension and left ventricular hypertrophy (LVH) are prone to develop heart failure. We tested the hypothesis that compensatory LVH is associated with normalization of myocardial oxygen consumption and that this occurs at the expense of a decrease in the ratio between cardiac work and oxygen consumption (efficiency). METHODS AND RESULTS Nine hypertensive men with LVH (LVH+) (age 42+/-2 years), left ventricular mass index (LVMI) 161+/-8 g/m(2), blood pressure (BP) 145+/-16/88+/-10 mm Hg (mean+/-SD); 8 hypertensive men without LVH (LVH-) (age 39+/-5 years, LVMI 107+/-15 g/m(2), BP 140+/-15/90+/-11 mm Hg); and 10 normotensive men (CONT) were studied. Myocardial blood flow, oxygen consumption, and glucose uptake were measured during euglycemic hyperinsulinemia using PET techniques. LV dimensions, volumes, and workload were determined by echocardiography, and efficiency was calculated. Myocardial workload (2.5+/-0.8 versus 3.0+/-0.6 versus 2. 3+/-0.5 mm Hg. mL. min(-1). g(-1) for CONT versus LVH- versus LVH+; P<0.05, LVH- versus LVH+), myocardial blood flow (0.84+/-0.16 versus 1.06+/-0.22 versus 0.81+/-0.09 mL. g(-1). min, respectively; P<0.05, LVH- versus other groups) and oxygen consumption (0.09+/-0.02 versus 0.14+/-0.03 versus 0.11+/-0.01 ml. g(-1). min(-1), respectively; P<0. 05, LVH- versus other groups) were increased in the LVH- group. Myocardial efficiency was reduced in the LVH+ group (18.1+/-4.1% versus 15.1+/-2.3% versus 13.5+/-1.9%, respectively; P<0.05, LVH+ versus CONT). CONCLUSIONS Myocardial oxygen consumption per unit weight is increased in hypertensive patients without LVH but is normal in those with LVH. The normalization of oxygen consumption via hypertrophy occurs at the expense of efficiency, which may predispose hypertensive patients with LVH to heart failure.

Insulin action on heart and skeletal muscle glucose uptake in weight lifters and endurance athletes.

There are no studies comparing myocardial metabolism between endurance- and resistance-trained athletes. We used 2-deoxy-2-[18F]fluoro-d-glucose and positron emission tomography combined with the euglycemic hyperinsulinemic clamp technique to compare the ability of insulin to stimulate myocardial, skeletal muscle, and whole body glucose uptake between weight lifters ( n = 8), endurance athletes ( n = 8), and sedentary men ( n = 9). Maximal aerobic power (ml ⋅ kg- 1 ⋅ min- 1) was higher in the endurance athletes (71 ± 2, P < 0.001) than the weight lifters (42 ± 2) and the sedentary men (42 ± 2). Skeletal muscle glucose uptake (μmol ⋅ kg muscle- 1 ⋅ min- 1) was enhanced in the endurance athletes (125 ± 16, P < 0.01) but was similar in weight lifters (59 ± 12) and sedentary (63 ± 7) men. The rate of glucose uptake per unit mass of myocardium (μmol ⋅ kg- 1 ⋅ min- 1) was similarly decreased in endurance athletes (544 ± 50) and weight lifters (651 ± 45) compared with sedentary men (1,041 ± 78, P < 0.001 vs. endurance athletes and weight lifters). Both groups of athletes had increased left ventricular mass. Consequently, total left ventricular glucose uptake was comparable in all groups. These data demonstrate that aerobic but not resistance training is associated with enhanced insulin sensitivity in skeletal muscle. Despite this, cardiac changes are remarkably similar in weight lifters and endurance athletes and are characterized by an increase in left ventricular mass and diminished insulin-stimulated glucose uptake per heart mass.

Fatty acid uptake is preserved in chronically dysfunctional but viable myocardium

Glucose uptake appears preserved or even enhanced in the chronically dysfunctional but viable myocardium. However, the use of other fuels such as free fatty acids (FFA) remains unknown. We studied FFA uptake in the chronically dysfunctional but viable myocardium in seven patients with an occluded major coronary artery and a corresponding chronic wall motion abnormality but no previous infarction. Myocardial FFA uptake kinetics in the fasting state were measured with positron emission tomography (PET) and 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid ([18F]FTHA). The FFA uptake index was calculated by multiplying the fractional [18F]FTHA uptake with serum FFA concentration. Myocardial blood flow (MBF) was measured with [15O]H2O and PET. Myocardial viability was confirmed with a static 18F-labeled 2-fluoro-2-deoxy-D-glucose PET imaging and a follow-up echocardiography in the revascularized patients. Regional MBF was slightly but not significantly lower in the dysfunctional compared with normal myocardial segments (0.76 +/- 0.18 vs. 0.81 +/- 0.14 ml.min-1.g-1, means +/- SD; P = 0.16). The fractional [18F]FTHA uptake rates [0.11 +/- 0.03 vs. 0.11 +/- 0.04 ml.g-1.min-1; not significant (NS)], and the FFA uptake indexes (5.8 +/- 1.7 vs. 5.8 +/- 2.1 mumol.100g-1.min-1; NS) were similar in the dysfunctional but viable and in the normal myocardial regions. Thus, in the chronically dysfunctional but viable (collateral-dependent) myocardium, the fatty acid uptake probed by [18F]FTHA appears preserved. Taken together with preserved glucose uptake, the results indicate that there is uncoupling of substrate uptake and mechanical function in the chronically dysfunctional but viable myocardium.Glucose uptake appears preserved or even enhanced in the chronically dysfunctional but viable myocardium. However, the use of other fuels such as free fatty acids (FFA) remains unknown. We studied FFA uptake in the chronically dysfunctional but viable myocardium in seven patients with an occluded major coronary artery and a corresponding chronic wall motion abnormality but no previous infarction. Myocardial FFA uptake kinetics in the fasting state were measured with positron emission tomography (PET) and 14( R, S)-[18F]fluoro-6-thia-heptadecanoic acid ([18F]FTHA). The FFA uptake index was calculated by multiplying the fractional [18F]FTHA uptake with serum FFA concentration. Myocardial blood flow (MBF) was measured with [15O]H2O and PET. Myocardial viability was confirmed with a static18F-labeled 2-fluoro-2-deoxy-d-glucose PET imaging and a follow-up echocardiography in the revascularized patients. Regional MBF was slightly but not significantly lower in the dysfunctional compared with normal myocardial segments (0.76 ± 0.18 vs. 0.81 ± 0.14 ml ⋅ min-1 ⋅ g-1, means ± SD; P = 0.16). The fractional [18F]FTHA uptake rates [0.11 ± 0.03 vs. 0.11 ± 0.04 ml ⋅ g-1 ⋅ min-1; not significant (NS)], and the FFA uptake indexes (5.8 ± 1.7 vs. 5.8 ± 2.1 μmol ⋅ 100 g-1 ⋅ min-1; NS) were similar in the dysfunctional but viable and in the normal myocardial regions. Thus, in the chronically dysfunctional but viable (collateral-dependent) myocardium, the fatty acid uptake probed by [18F]FTHA appears preserved. Taken together with preserved glucose uptake, the results indicate that there is uncoupling of substrate uptake and mechanical function in the chronically dysfunctional but viable myocardium.

Preserved Relative Dispersion but Blunted Stimulation of Mean Flow, Absolute Dispersion, and Blood Volume by Insulin in Skeletal Muscle of Patients With Essential Hypertension

BACKGROUND We examined the integrity of the effects of insulin on mean muscle blood flow, flow heterogeneity, and blood volume in essential hypertension. METHODS AND RESULTS Positron emission tomography, combined with [15O]H2O and [15O]CO as tracers for direct measurement of blood flow and volume in skeletal muscle, and a new bayesian iterative reconstruction algorithm allowing pixel-by-pixel quantitation of blood flow and flow dispersion, were used. Measurements were performed basally after an overnight fast and under normoglycemic hyperinsulinemic conditions in 11 newly diagnosed, untreated mildly hypertensive men (age, 35 +/- 1 years; body mass index, 25.2 +/- 0.4 kg/m2, blood pressure 141 +/- 4/96 +/- 2 mm Hg, mean +/- SE) and 11 matched normotensive men. Insulin-stimulated whole body glucose uptake was significantly decreased in the hypertensive men (41 +/- 4 mumol/kg per minute) compared with the normotensive (59 +/- 4 mumol/kg per minute, P < 0.005) men. Mean blood flow in skeletal muscle was significantly lower in the hypertensive than the normal subjects basally (1.7 +/- 0.2 versus 2.7 +/- 0.4 mL/0.1 kg per minute, P < 0.05) and during hyperinsulinemia (2.3 +/- 0.2 versus 4.2 +/- 0.8, P < 0.05). The flow response to insulin (0.6 +/- 0.2 versus 1.9 +/- 0.5 mL/0.1 kg per minute, hypertensive versus normal subjects, P < 0.05) was also significantly blunted. Muscle blood volume was significantly lower in the hypertensive than in the normal subjects, both basally (3.0 +/- 0.2 versus 3.5 +/- 0.2 mL/0.1 kg, P < 0.05) and during hyperinsulinemia (3.1 +/- 0.2 versus 4.0 +/- 0.2 mL/0.1 kg muscle, P < 0.02). The increase in muscle blood volume by insulin was significant in the normal (P < 0.05) but not the hypertensive subjects. Regional pixel-by-pixel analysis within femoral muscles revealed significant spatial heterogeneity of blood flow. Insulin increased absolute dispersion of blood flow significantly more in the normal subjects than in the hypertensive subjects (P < 0.05). CONCLUSIONS True flow heterogeneity, as judged from the coefficients of variation (relative dispersion), was comparable between the groups basally and during hyperinsulinemia. We conclude that mean flow, its absolute dispersion, and blood volume exhibit insulin resistance in patients with essential hypertension.

Myocardial blood flow, oxygen consumption, and fatty acid uptake in endurance athletes during insulin stimulation

We have previously demonstrated reduced myocardial glucose uptake rates in hearts of endurance athletes, which could be due to increased use of alternative fuels or reduced energy demands. In the present study myocardial blood flow, oxygen consumption, and free fatty acid uptake were measured with [(15)O]H(2)O, [(15)O]O(2), [(18)F]FTHA, and positron emission tomography (PET) in 9 endurance athletes and 11 sedentary men during euglycemic hyperinsulinemia. Compared with sedentary men, athletes had 33% lower myocardial blood flow, 27% lower oxygen consumption, and 20% lower estimated myocardial work per gram of tissue. Myocardial fatty acid uptake rates were not significantly different in endurance athletes (0.83 +/- 0.29) and sedentary men (1.0 +/- 0.31 micromol. 100 g(-1). min(-1), P = 0.232). In conclusion, myocardial blood flow and oxygen consumption per unit mass of myocardium are reduced at rest in endurance athletes. This can be explained by reduced energy requirements per gram of tissue due to anatomic and physiological changes of the athletes heart.We have previously demonstrated reduced myocardial glucose uptake rates in hearts of endurance athletes, which could be due to increased use of alternative fuels or reduced energy demands. In the present study myocardial blood flow, oxygen consumption, and free fatty acid uptake were measured with [15O]H2O, [15O]O2, [18F]FTHA, and positron emission tomography (PET) in 9 endurance athletes and 11 sedentary men during euglycemic hyperinsulinemia. Compared with sedentary men, athletes had 33% lower myocardial blood flow, 27% lower oxygen consumption, and 20% lower estimated myocardial work per gram of tissue. Myocardial fatty acid uptake rates were not significantly different in endurance athletes (0.83 ± 0.29) and sedentary men (1.0 ± 0.31 μmol ⋅ 100 g-1 ⋅ min-1, P = 0.232). In conclusion, myocardial blood flow and oxygen consumption per unit mass of myocardium are reduced at rest in endurance athletes. This can be explained by reduced energy requirements per gram of tissue due to anatomic and physiological changes of the athletes heart.

Myocardial blood flow and adenosine A2A receptor density in endurance athletes and untrained men

Previous human studies have shown divergent results concerning the effects of exercise training on myocardial blood flow (MBF) at rest or during adenosine‐induced hyperaemia in humans. We studied whether these responses are related to alterations in adenosine A2A receptor (A2AR) density in the left‐ventricular (LV) myocardium, size and work output of the athletes heart, or to fitness level. MBF at baseline and during intravenous adenosine infusion, and A2AR density at baseline were measured using positron emission tomography, and by a novel A2AR tracer in 10 healthy male endurance athletes (ET) and 10 healthy untrained (UT) men. Structural LV parameters were measured with echocardiography. LV mass index was 71% higher in ET than UT (193 ± 18 g m−2versus 114 ± 13 g m−2, respectively). MBF per gram of tissue was significantly lower in the ET than UT at baseline, but this was only partly explained by reduced LV work load since MBF corrected for LV work was higher in ET than UT, as well as total MBF. The MBF during adenosine‐induced hyperaemia was reduced in ET compared to UT, and the fitter the athlete was, the lower was adenosine‐induced MBF. A2AR density was not different between the groups and was not coupled to resting or adenosine‐mediated MBF. The novel findings of the present study show that the adaptations in the heart of highly trained endurance athletes lead to relative myocardial ‘overperfusion’ at rest. On the other hand hyperaemic perfusion is reduced, but is not explained by A2AR density.

Exercise Echocardiography in the Diagnosis of Coronary Artery Disease

The purpose of this study was to test the applicability of exercise echocardiography in the diagnosis of coronary artery disease. The results were compared to findings of coronary angiography. 118 patients, 100 males and 18 females, who were all referred to coronary angiography for suspected ischaemic heart disease, underwent exercise echocardiography using a cycle ergometer. At coronary angiography 108 patients had significant stenosis in at least one coronary artery. Ten patients had angiographically normal coronary arteries. A new or increased wall motion abnormality detected by echocardiography after the exercise was considered an ischaemic response. Of the 108 patients with coronary artery disease, 101 had abnormal exercise echocardiograms, and the overall sensitivity of exercise echocardiography in detecting ischaemic heart disease was 94%. Among the 10 patients without coronary artery disease, seven had normal and three had abnormal exercise echocardiograms, and the specificity of the test was 70%. In conclusion, exercise echocardiography is a reliable diagnostic method in screening of ischaemic heart disease, and it can be combined relatively easily with the exercise examinations.