The effect of revascularization of atherosclerotic renal artery stenosis on coronary flow reserve and peripheral endothelial function.

BACKGROUND: Patients with atherosclerotic renovascular disease (ARVD) are at increased risk of heart disease because of associated hypertension, coronary artery disease, cardiac failure and chronic kidney disease. Although suggested to be beneficial, the cardiac effects of renal artery revascularization have not been well characterized. Our aim was to analyze the effects of percutaneous dilatation of renal artery stenosis (RAS) in ARVD patients on coronary and peripheral vascular function. METHODS: Nineteen ARVD patients [11 females and 8 males, age at study entry (mean ± SD) 69 ± 10 years] were treated by dilatation of unilateral (n = 9) or bilateral (n = 10) RAS, mainly because of uncontrolled or refractory hypertension. The patients were studied before and after the procedure (103 ± 29 days). They underwent echocardiography and peripheral artery endothelial function testing using flow-mediated dilatation (FMD) of brachial artery at rest and during reactive hyperemia. Myocardial blood flow was measured using quantitative PET perfusion imaging at baseline and during dipyridamole-induced hyperemia. RESULTS: Peripheral endothelial function, tested by FMD, as well as systolic blood pressure and left ventricular mass were improved in patients with bilateral RAS. However, myocardial perfusion and coronary flow reserve (CFR) did not change after the RAS dilatation. CONCLUSION: This is the first study to analyze the stage of myocardial perfusion and CFR in ARVD patients. Although peripheral endothelial function, systolic blood pressure and left ventricular hypertrophy were improved in patients with bilateral RAS by revascularization of RAS, it did not have any effect on coronary perfusion.

Short-term changes in inflammatory response protein (hsCRP) do not parallel with changes in coronary vasoreactivity in obese men.

AIM: Obese subjects are characterized by increased high-sensitivity C-reactive protein (hsCRP) and coronary vascular resistance. Clucocorticoids suppress inflammation, a possible cardioprotective effect. We tested the short-term anti-inflammatory effect of dexamethasone (dx) on these parameters in obese subjects. METHODS: Coronary vascular resistance was quantitated basally and during adenosine infusion with or without simultaneous euglycemic hyperinsulinemic clamp (insulin infusion rate of 1 mU/kg/min) in 11 obese and 19 age-matched nonobese males using positron emission tomography and (15)O-water. Each subject was studied both with and without previous dx treatment for 2 days (2 mg/day). RESULTS: Before dx treatment, hsCRP concentration was significantly higher in obese than in nonobese subjects (1.55+/-1.73 vs 0.32+/-0.32 mg/l, P = 0.005). In addition, coronary vascular resistances were higher (P < 0.05) in obese than in nonobese subjects at baseline (139+/-36 vs 117+/-22) and during adenosine infusion without (32+/-7 vs 26+/-7) or with simultaneous clamp (26+/-8 vs 21+/-5 mmHg min g/ ml). Dx treatment decreased significantly hsCRP concentration in obese but not in nonobese subjects, leading to similar hsCRP concentrations between the groups (0.45+/-0.43 vs 0.26+/-0.42 mg/l, respectively, P = 0.3). Dx had no effect on coronary vascular resistances (NS). CONCLUSIONS: Obese subjects are characterized by high hsCRP, which can be normalized by dx. However, despite this, coronary vascular resistances did not decrease in obese subjects. Short-term changes in inflammatory response protein appear not to parallel with changes in coronary vasoreactivity in obese men.

Lifetime glycaemic exposure predicts reduced coronary vasoreactivity in Type 1 diabetic subjects.

AIMS: Subjects with Type 1 diabetes have impaired coronary vasoreactivity but the independent role of glycaemic control on myocardial perfusion is less clear. We examined the effect of lifetime glycaemic exposure on coronary vasoreactivity in 43 otherwise healthy Type 1 diabetic subjects. METHODS: Myocardial blood flow was calculated basally and during pharmacologically induced hyperaemia in the fasting state and during euglycaemic hyperinsulinaemic clamp (at an insulin infusion rate of 1 mU/kg per min for 60 min) using positron emission tomography and (15)O-water. Glycaemic exposure was estimated as glycosylated haemoglobin A(1c) (HbA(1c)) months. RESULTS: Hyperaemic myocardial blood flow was inversely associated with log HbA(1c) months in the fasting state (r = -0.72, P < 0.01) and during clamp (r = -0.35, P < 0.05). These correlations remained significant after adjustment for lipid values, blood pressures, sex, smoking, body mass index (BMI) and age (r = -0.70, P < 0.05 and r = -0.35, P < 0.05, respectively). No significant correlation was detected between hyperaemic flow and HbA(1c) or plasma glucose values measured immediately preceding the PET study. CONCLUSIONS: The present study demonstrates that the lifetime glycaemic exposure appears to be a better predictor of reduced coronary vasoreactivity than recent glycaemic control in Type 1 diabetic subjects. Reduced coronary vasoreactivity in diabetic subjects with poor glycaemic control and/or long duration of diabetes may represent an early precursor of coronary artery disease.

High-sensitivity C-reactive protein and impaired coronary vasoreactivity in young men with uncomplicated type 1 diabetes.

AIMS/HYPOTHESIS: Elevated high-sensitivity C-reactive protein (hsCRP) concentrations indicate increased risk of future coronary events. The association between hsCRP and coronary vasoreactivity has not yet been examined in type 1 diabetic subjects. METHODS: We studied 18 young men who were non-smokers and who had uncomplicated type 1 diabetes. The diabetic subjects were divided into two groups, according to their median hsCRP concentration, as follows: (i) subjects with slightly elevated hsCRP (median 0.76 mg/l, range 0.47-4.73 mg/l, n=8); and (ii) subjects with low hsCRP (median 0.32 mg/l, range 0.11-0.35 mg/l, n=10). In addition we investigated 22 non-diabetic age-matched subjects (hsCRP: median 0.42 mg/l, range 0.11-1.31 mg/l). Resting myocardial blood flow and hyperaemic adenosine-stimulated flow during euglycaemic-hyperinsulinaemic clamp were determined using positron emission tomography and oxygen-(15)-labelled water. RESULTS: Diabetic subjects with slightly elevated hsCRP had significantly higher hsCRP concentrations than non-diabetic subjects (p=0.008). Resting myocardial blood flow was similar (NS) in diabetic subjects with slightly elevated hsCRP (0.79+/-0.19 ml.g(-1).min(-1)) or low hsCRP (0.81+/-0.15 ml.g(-1).min(-1)) and non-diabetic subjects (0.80+/-0.19 ml.g(-1).min(-1)). Adenosine infusion induced a significant increase in blood flow in all study subjects (p<0.001) but was blunted in diabetic subjects with slightly elevated hsCRP (3.42+/-0.61 ml.g(-1).min(-1)) when compared with diabetic subjects with low hsCRP (5.08+/-1.65 ml.g(-1).min(-1), p=0.02) or non-diabetic subjects (4.51+/-1.36 ml.g(-1).min(-1), p=0.04). Adenosine-stimulated flow was inversely correlated with hsCRP concentrations in all diabetic subjects (r=-0.70, p=0.001). CONCLUSIONS/INTERPRETATION: In young subjects with uncomplicated type 1 diabetes, even slightly elevated hsCRP concentrations are associated with reduced coronary vasoreactivity.

Insulin induced increase in coronary flow reserve is abolished by dexamethasone in young men with uncomplicated type 1 diabetes.

OBJECTIVE: To examine the role of the sympathetic nervous system in regulating insulin's action on coronary perfusion in uncomplicated type 1 diabetes by blocking centrally mediated sympathetic activity with dexamethasone. METHODS: Positron emission tomography and oxygen 15 labelled water were used to quantify myocardial blood flow basally and during adenosine infusion with or without simultaneous euglycaemic physiological hyperinsulinaemia in nine non-smoking men with type 1 diabetes and 12 healthy non-diabetic men. Each patient was studied both with and without previous dexamethasone treatment for two days (2 mg/day). RESULTS: Insulin increased coronary flow reserve in diabetic (from 4.3 (0.7) to 5.1 (0.6), p < 0.05) and non-diabetic (from 4.3 (0.3) to 5.4 (0.4), p < 0.05) patients. In contrast to non-diabetic patients dexamethasone pretreatment abolished the insulin induced increase in coronary flow reserve in diabetic patients (p < 0.05) leading to lower coronary flow reserve in diabetic than in non-diabetic patients (3.9 (0.6) v 7.1 (0.9), p < 0.05). CONCLUSIONS: These results show that insulin's ability to modulate coronary perfusion is sustained in young patients with type 1 diabetes without microvascular complications or autonomic neuropathy. Dexamethasone treatment abolished the insulin induced increase in coronary flow reserve in diabetic patients but not in healthy study participants, suggesting that sympathetic activation plays an important part in regulating insulin's effects on myocardial perfusion in patients with type 1 diabetes.

The effects of insulin and short-term hyperglycaemia on myocardial blood flow in young men with uncomplicated Type I diabetes.

AIMS/HYPOTHESIS: Insulin enhances coronary vasodilation in healthy subjects. We tested whether insulin is able to induce coronary vasodilation in Type I (insulin-dependent) diabetic mellitus patients. Additionally, the effect of short-term hyperglycaemia on myocardial perfusion was studied. METHODS: Myocardial blood flow was quantitated basally and during adenosine infusion (140 microg/kg per min i.v.) with or without simultaneous insulin infusion (1 mU/kg per min for 60 min) in nine non-smoking Type I diabetic males (HbA(1c) 7.4+/-1.0%) without diabetic complications and 10 healthy non-diabetic otherwise matched males using positron emission tomography and (15)O-water. Diabetic patients were studied on two occasions, once during normoglycaemia (plasma glucose ~6 mmol/l) and once during hyperglycaemia (approximately 10 mmol/l) induced by reducing the dose of insulin for two days. RESULTS: Resting myocardial blood flow was similar in the studied groups (NS). Hyperaemic adenosine stimulated flow was 23% lower in diabetic than in non-diabetic subjects (3.09+/-0.72 vs 4.0+/-1.13 ml x g(-1) x min(-1), p<0.05). Insulin increased significantly adenosine stimulated flow by 23% in diabetic and 17% in non-diabetic subjects (NS between the groups). Hyperglycaemia for two days had no effect on flow values when compared to the values during normoglycaemia (NS). CONCLUSION/INTERPRETATION: Insulin has similar vasodilative effects on coronary arteries in diabetic and non-diabetic subjects. Short-term hyperglycaemia does not alter myocardial blood flow or abolish insulin induced vasodilation in these patients. Insulin induced coronary vasodilation might contribute to the known beneficial effect of intensive insulin therapy on myocardial ischaemia in diabetic patients.

Adenosine in myocardial protection given through three windows of opportunity. An experimental study with pigs.

OBJECTIVE: Adenosine (ADO) has been shown to have beneficial effects against tissue injury after myocardial ischemia. However, the timing and dose of ADO administration have not been defined. This study was designed to determine the cardioprotective effect of exogenous ADO in an experimental open heart surgery model in pigs. DESIGN: The animals were openly divided into two groups both undergoing 30 min of total cardiac arrest. In the control group animals received cold crystalloid cardioplegic solution. In the ADO group ADO was added to cardioplegic solution and in addition ADO was infused to the superior vena cava for 2 h starting 30 min before cardiac arrest. The pumping function of the heart was measured with echocardiography and myocardial blood flow was measured with microspheres and positron emission tomography (PET). Cardiomyocyte apoptosis was detected and tumor necrosis factor (TNF) levels were measured. RESULTS: Better post-ischemic pumping function was found in the ADO group (relative decrease 43.7% vs 55.4%, p = 0.20 between the groups). The cardiac output decreased significantly from the baseline values (p < 0.05 in both groups). There was a temporary decrease in myocardial blood flow post-ischemically, followed by a compensatory increase during the later reperfusion period. The cardiomyocyte apoptosis was induced significantly in both groups. CONCLUSIONS: In this experiment two important details were noticed. Firstly, cardiomyocyte apoptosis is involved in ischemia-reperfusion injury associated with open heart surgery. Secondly, PET is a comparable method with the microsphere technique when coronary flow is studied. No significant effects of ADO against ischemia-reperfusion injury could be shown. However, there were some signsof positive outcome, even though statistical significance could not be reached.

Insulin-induced increment of coronary flow reserve is not abolished by dexamethasone in healthy young men.

Hyperinsulinemia is a risk factor for coronary artery disease. Previous studies have reported that hyperinsulinemia increases cardiac and skeletal muscle sympathetic nerve activity and skeletal muscle blood flow in normal subjects. However, little is known about insulin's effects on myocardial blood flow in humans. The purpose of this study was to investigate whether physiological hyperinsulinemia affects myocardial blood flow and flow reserve in healthy subjects. Additionally, the role of the sympathetic nervous system in regulating insulin's effects on coronary perfusion was tested. We used positron emission tomography and oxygen-15-labeled water to measure myocardial blood flow and coronary flow reserve in 16 healthy nonobese men (age, 34 +/- 4 yr; maximal aerobic capacity, 32 +/- 3 mL x g(-1) x min(-1); blood pressure, 118 +/- 10/65 +/- 8 mm Hg) at fasting and during euglycemic hyperinsulinemic clamp (1 mU x kg(-1) x min(-1) for 80 min). To study the role of the sympathetic nervous system, each subject was studied twice: once after administration of dexamethasone (dexa+) for 2 days (2 mg per day) and once without previous medication (dexa-). All studied subjects had normal left ventricular mass, function, and findings in stress echocardiography. Resting myocardial blood flow was 0.76 +/- 0.19 mL x g(-1) x min(-1), and a significant increase in flow was detected after adenosine infusion (140 microg/kg x min for 5 min i.v.), both in the basal fasting state (P < 0.001) and during hyperinsulinemia (P < 0.001). However, the flow response to adenosine was significantly higher during hyperinsulinemia, thus leading to a higher hyperemic flow (3.38 +/- 0.97 vs. 4.28 +/- 1.57 mL x g(-1) x min(-1), basal vs. hyperinsulinemic, P < 0.01) and higher coronary flow reserve (4.6 +/- 1.2 vs. 5.8 +/- 1.9, respectively, P < 0.05). Pretreatment with dexamethasone did not significantly change the resting blood flow [0.72 +/- 0.22 vs. 0.76 +/- 0.19 mL x g(-1) x min(-1), dexa+ vs. dexa-, not significant (NS)], the adenosine stimulated flow (3.56 +/- 1.49 vs. 3.38 +/- 0.97 mL x g(-1) x min(-1), respectively, NS), or the hyperinsulinemic adenosine-stimulated blood flow (4.68 +/- 1.74 vs. 4.28 +/- 1.57 mL x g(-1) x min(-1), respectively, NS). Coronary flow reserves in the basal state (5.3 +/- 2.7 vs. 4.6 +/- 1.2 mL x g(-1) x min(-1), dexa+ vs. dexa-, NS) and during hyperinsulinemia (6.8 +/- 2.9 vs. 5.8 +/- 1.9 mL x g(-1) x min(-1), respectively, NS) tended to be (but were not) significantly higher after dexamethasone treatment. These results demonstrate that insulin acts as a vasodilatory hormone also in the coronary vasculature. Because the insulin-induced increment of myocardial flow reserve remained unchanged by dexamethasone pretreatment, centrally mediated sympathetic activation seems not to play a major role in regulating insulin action on myocardial perfusion in healthy subjects.

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.

Is routine echocardiography useful in patients hospitalized for chest pain? Evidence of areal myocardial dysfunction detected only by echocardiography.

To assess the diagnostic value of routine two-dimensional echocardiography in the coronary care unit setting, we studied 81 unselected patients admitted for acute chest pain. Using electrocardiography (ECG), clinical history and serum markers of myocardial injury, the patients were retrospectively diagnosed as having had definite acute myocardial infarction (AMI) with (n=13) or without (n=31) previous infarction, possible AMI with (n=14) or without (n=15) previous infarction, and non-coronary cardiac or other causes of chest pain (n=8). Abnormal wall motion was observed in 75/77 patients with a cardiac origin of symptoms (sensitivity 97%), and there were no false-positive wall motion findings. In the 73 patients who were finally diagnosed with coronary artery disease (CAD), echocardiography showed wall motion abnormality in at least one additional coronary territory area in which there were no diagnostic ECG changes for 56% of patients with CAD (41/73) (P<0. 001). These areas were considered to be indicative of the presence of myocardium at risk for future cardiac events. We conclude that in addition to being a sensitive and accurate tool for detection of ischaemic wall motion abnormalities, two-dimensional echocardiography can give valuable information about the area of myocardium at risk. Therefore, therapeutic decisions can be affected by the findings of the routine echocardiographic examination, which is recommended even in unselected coronary care unit patients.

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 athlete's heart.

Impaired free fatty acid uptake in skeletal muscle but not in myocardium in patients with impaired glucose tolerance: studies with PET and 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid.

Free fatty acids (FFAs) are an important substrate for myocardial and skeletal muscle metabolism, and increased availability and oxidation of FFA are suggested to be associated with insulin resistance. This study was undertaken to assess whether myocardial or muscle uptake of FFA is altered in patients with impaired glucose tolerance (IGT). Eight healthy men (control group; age 48+/-1 years, BMI 25+/-1 kg/m2, mean +/- SE) and eight men with IGT (glucose-intolerant group; age 49+/-1 years, BMI 29+/-1 kg/m2) were studied in the fasting state. Myocardial oxygen consumption and blood flow and myocardial and femoral muscle FFA uptake rates were measured with positron emission tomography (PET) and [15O]O2, [15O]H2O, [15O]CO, and 14(R, S)-[18F]fluoro-6-thia-heptadecanoic acid ([18F]FTHA), a fatty acid tracer trapped into the cell after undergoing initial steps of beta-oxidation. Serum glucose and insulin concentrations were higher in the glucose-intolerant group during the PET study, but FFA concentrations were comparable between the groups. No differences between the groups were observed in the myocardial blood flow, oxygen consumption, fractional FTHA uptake rates, or FFA uptake indices (5.6+/-0.4 vs. 5.2+/-0.4 pmol x 100 g(-1) x min(-1), glucose-intolerant versus control, NS). In the femoral muscle, fractional FTHA uptake (0.0062+/-0.0003 vs. 0.0072+/-0.0003 min(-1), P = 0.044) and FFA uptake indices (0.30+/-0.02 vs. 0.43+/-0.04 min(-1), P = 0.020) were significantly lower in the glucose-intolerant group than in the control group. In conclusion, when studied at the fasting state and normal serum FFA concentrations, subjects with IGT have similar myocardial but lowered femoral muscle FFA uptake. This finding argues against the hypothesis that an increased oxidation of serum FFA, via the competition of glucose and FFA as fuel sources, is the primary cause for impaired peripheral glucose utilization and insulin resistance commonly observed in IGT.

Automated electrocardiographic scores to estimate myocardial injury size during the course of acute myocardial infarction.

The automated ST-elevation score at admission and maximal QRS score during hospitalization provide good estimates of biochemical injury size during the course of first myocardial infarction. Being easily computerized, such scores could be used routinely to monitor the effect of injury-limiting therapy.

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 (micromol. 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 (micromol. 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.

Free fatty acid uptake in the myocardium and skeletal muscle using fluorine-18-fluoro-6-thia-heptadecanoic acid.

UNLABELLED: 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (FTHA) has been recently introduced as a new tracer for fatty acid metabolism. Myocardial [18F]FTHA uptake is believed to reflect mainly beta-oxidation of the circulating free fatty acids (FFAs), since it is trapped in the mitochondria because subsequent steps of beta-oxidation are inhibited by sulfur heteroatom. We investigated [18F]FTHA kinetics in myocardial and skeletal muscle in vivo. METHODS: Two dynamic PET studies were performed in seven patients with stable coronary artery disease, once in the fasting state and once during euglycemic hyperinsulinemia (serum insulin approximately 60 mU/liter). The fractional [18F] FTHA uptake rates (Ki) were multiplied with serum FFA concentrations and were considered to represent FFA uptake. RESULTS: Serum FFA concentration decreased by 80% during insulin clamp. After tracer injection, rapid myocardial uptake was identified both in the fasting state and during insulin stimulation. The cardiac image quality was excellent in both occasions. In addition, femoral muscles were clearly visualized in both studies. The fractional myocardial [18F]FTHA uptake rates (Ki) in the normal myocardial regions were similar in the fasting state (0.11 +/- 0.04 ml/g/min (mean +/- s.d.) and during insulin clamp (0.12 +/- 0.03 ml/g/min; ns). The calculated myocardial FFA uptake was four times higher in the fasting state than during insulin clamp (5.8 +/- 1.7 versus 1.4 +/- 0.5 micromol/100 g/min, p < 0.005). The femoral muscle fractional [18F]FTHA uptake rates (Ki) were lower (0.0071 +/- 0.0014 ml/g/min) in the fasting state than during insulin clamp (0.0127 +/- 0.0036 ml/g/min; p = 0.03), but the estimated femoral muscle FFA uptake was three times higher in the fasting state (0.38 +/- 0.09 micromol/100 g/min) as compared to that during insulin clamp (0.12 +/- 0.05 micromol/100 g/min, p < 0.005). CONCLUSION: Fluorine-18-FTHA PET appears to be a feasible method to estimate fatty acid kinetics in myocardial and skeletal muscle. Physiologically reasonable rates of FFA uptake in myocardium and skeletal muscle were obtained. Furthermore, the uptake rates were suppressed in response to insulin both in the myocardial and femoral muscle as expected.

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.

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

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 micromol/kg body weight min) than the normal subjects (45+/-3 micromol/kg body weight x min, p < 0.02). Insulin-stimulated femoral muscle glucose uptake was significantly lower in the patients with NIDDM (71+/-6 micromol/kg muscle x min) than in the normal subjects (96+/-5 micromol/kg muscle x 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 micromol/kg muscle min) and the normal subjects (731+/-63 micromol/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.

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 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.

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.