Mikko J. Järvisalo

Endothelial Dysfunction and Increased Arterial Intima-Media Thickness in Children With Type 1 Diabetes

Background—Endothelial dysfunction may play a pathophysiological role in the development of atherosclerosis in subjects with type 1 diabetes. We examined whether alterations in vascular endothelial function exist in children with type 1 diabetes and tested the hypothesis that endothelial dysfunction is associated with early structural atherosclerotic vascular changes in these children. Methods and Results—Noninvasive ultrasound was used to measure brachial artery flow-mediated dilation (FMD) responses and carotid artery intima-media thickness (IMT) in 75 children (mean age 11±2 years), 45 with type 1 diabetes (diabetes duration 4.4±2.9 years) and 30 healthy control children. Children with diabetes had lower peak FMD response (4.4±3.4% versus 8.7±3.6%, P <0.001) and increased IMT (P <0.001) compared with controls. Sixteen children with diabetes (36%) had endothelial dysfunction defined as total FMD response in the lowest decile for normal children. These children had increased carotid IMT (0.58±0.05 versus 0.54±0.04 mm, P =0.01) and higher LDL cholesterol concentration (2.63±0.76 versus 2.16±0.60 mmol/L, P =0.03) compared with diabetic children without endothelial dysfunction. Multivariate correlates of increased IMT included diabetes group (P =0.03), low FMD (P =0.03), and high LDL cholesterol (P =0.08). Conclusions—Impaired FMD response is a common manifestation in children with type 1 diabetes and is associated with increased carotid artery IMT. These data suggest that endothelial dysfunction in children with type 1 diabetes may predispose them to the development of early atherosclerosis.

Elevated Serum C-Reactive Protein Levels and Early Arterial Changes in Healthy Children

Objective—Elevated serum concentration of C-reactive protein (CRP) predicts cardiovascular events in adults. Because atherosclerosis begins in childhood, we undertook a study to determine whether changes in brachial artery endothelial function and the thickness of the carotid intima-media complex, 2 markers of early atherosclerosis, are related to CRP levels in healthy children. Methods and Results—Brachial artery flow-mediated dilatation (FMD) and carotid artery intima-media thickness (IMT) were measured with ultrasound in 79 children (aged 10.5±1.1 years). Compared with the children with CRP levels under the detection limit (<0.1 mg/L, n=40, group 1), the children with higher CRP (0.1 mg/L≤CRP≤0.7 mg/L, n=20, group 2; CRP >0.7 mg/L, n=19, group 3) had lower FMD (9.0±4.4% versus 7.8±3.3% versus 6.5±2.6%, respectively;P =0.015 for trend) and greater carotid IMT (0.45±0.03 versus 0.46±0.04 versus 0.49±0.06 mm, respectively, P =0.002 for trend). CRP level remained a statistically significant independent predictor for brachial FMD and carotid IMT in multivariate analyses. Conclusions—These data suggest that CRP affects the arteries of healthy children by disturbing endothelial function and promoting intima-media thickening. The findings support the hypothesis that CRP plays a role in the pathogenesis of early atherosclerosis.

Risk Factors Identified in Childhood and Decreased Carotid Artery Elasticity in Adulthood The Cardiovascular Risk in Young Finns Study

Background—Exposure to risk factors in childhood may have long-term influences on vascular function. We examined the relationship between risk factors identified in childhood and arterial elasticity assessed in adulthood. Methods and Results—Carotid artery compliance (CAC), Young’s elastic modulus (YEM), and stiffness index (SI), 3 measures of large-artery elasticity, were assessed with noninvasive ultrasound in 2255 healthy white adults aged 24 to 39 years participating in a population-based cohort study and who had risk factor data available since childhood. In multivariate models, childhood obesity (skinfold thickness) predicted decreased CAC (P<0.001), increased YEM (P<0.01), and increased SI (P<0.01) in adulthood. Childhood blood pressure was inversely associated with CAC (P<0.001) and directly associated with YEM (P<0.001). The number of risk factors identified in childhood, which included high LDL cholesterol (at or above 80th percentile), elevated blood pressure, skinfold thickness, low HDL cholesterol (at or below 20th percentile), and smoking, was related inversely with CAC (P<0.001) and directly with YEM (P<0.001). These associations remained highly significant after adjustment for the number of risk factors identified in adulthood (P=0.005 for CAC and P<0.001 for YEM). Conclusions—Cardiovascular risk factors identified in childhood and adolescence predict decreased carotid artery elasticity in adulthood. These data suggest that risk factors operating in early life may have sustained deleterious effects on arterial elasticity.

Determinants of Arterial Nitrate-Mediated Dilatation in Children Role of Oxidized Low-Density Lipoprotein, Endothelial Function, and Carotid Intima-Media Thickness

Background—Impaired arterial dilatation response to nitroglycerin has been observed in adults with risk factors for atherosclerosis and in patients with established atherosclerotic disease. This defect parallels changes in vascular endothelial function and may be attributed to increased oxidative stress. Because atherosclerosis begins in childhood, we examined the correlates of nitrate-mediated dilatation (NMD) in children, including brachial artery endothelial function, oxidized LDL, and carotid artery intima-media thickness (IMT). Methods and Results—Brachial artery flow-mediated endothelium-dependent dilatation (FMD) and nitrate-mediated smooth muscle function, IMT of the carotid bulb, and brachial artery and oxidized LDL were measured in 142 children (mean age, 11 years; range, 8 to 17 years), including 87 healthy children, 41 diabetic children, and 14 children with familial hypercholesterolemia. NMD correlated directly with FMD (r=0.46, P<0.001) and inversely with brachial artery baseline diameter (r=−0.36, P<0.001), age (r=−0.25, P=0.003), body mass index (r=−0.31, P<0.001), diabetes (r=−0.22, P=0.008), oxidized LDL (r=−0.18, P=0.045), and IMT (r=−0.33, P<0.001). In a multivariate regression model, the significant correlates for NMD were FMD response (β=0.003, P<0.001), brachial artery diameter (β=−0.03, P=0.01), oxidized LDL (β=−0.07, P=0.02), and IMT (β=−0.15, P=0.03). Conclusions—Reduced endothelial function, increased oxidative stress, and preclinical carotid atherosclerosis are independent determinants of impaired NMD in children. These data thus suggest that primary nitrate tolerance occurs in children at risk for atherosclerosis.

HMG CoA reductase inhibitors are related to improved systemic endothelial function in coronary artery disease

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (statins) may enhance vascular endothelial function independent of their cholesterol lowering effect. To test this hypothesis, we surveyed two groups of patients (age 55+/-7, mean+/-SD) with coronary artery disease that were matched for age, blood pressure and serum lipid levels. Group 1 comprised 23 men without lipid-lowering medication and Group 2 included 22 patients with ongoing HMG CoA reductase inhibitor medication. Flow-mediated (endothelium-dependent) arterial dilatation (FMD) and nitrate-mediated (smooth muscle dependent) dilatation (NMD) were measured in the brachial artery using high resolution ultrasound. FMD was considerably higher in group 2 (4.3+/-2.6 vs. 2.6+/-2.8%; P<0.05). In multivariate regression model, statin use was the only significant (P<0.05) predictor of FMD. In all subjects, FMD correlated with statin dose (P<0.05 for trend). NMD was non-significantly higher in group 2 (11.4+/-5.0 vs. 9.0+/-4.2%, P=0. 08). We conclude that patients with established coronary artery disease on HMG CoA reductase inhibitor therapy have better vascular endothelial function than similar patients without the medication. These data provide further support for the idea that HMG CoA reductase inhibitors enhance endothelial function independent of their lipid-lowering effects. This may suggest that these drugs could be beneficial in secondary prevention of coronary artery disease regardless of the serum cholesterol concentration.

Endothelial Function in Healthy 11-Year-Old Children After Dietary Intervention With Onset in Infancy The Special Turku Coronary Risk Factor Intervention Project for Children (STRIP)

Background— Early childhood introduction of nutritional habits aimed at atherosclerosis prevention reduces children’s serum total cholesterol concentration, but its effect on vascular endothelial function is unknown. Methods and Results— Between 1990 and 1992, we randomized healthy 7-month-old infants (n=1062) to intervention (low-saturated-fat diet) and control (unrestricted diet) groups. At the age of 11 years, endothelium-dependent (flow-mediated) and endothelium-independent (nitrate-mediated) vasodilatory responses of the brachial artery were measured with high-resolution ultrasound in 179 intervention and 190 control children. The effect of intervention on endothelial function was significant in boys (P=0.0034) but not in girls (P=0.69). The maximum endothelium-dependent dilation response (mean±SD) was 9.62±3.53% and 8.36±3.85% in intervention boys and control boys and 8.84±4.00% and 8.44±3.60% in intervention girls and control girls, respectively. Intervention had no effect on nitrate-mediated dilation. The difference in endothelial function in boys remained significant after adjustment for current serum total or LDL cholesterol but became nonsignificant after adjustment for mean cholesterol measured under 3 years of age (adjusted means: 9.46% [CI 8.68% to 10.24%] versus 8.54% [CI 7.75% to 9.32%], P=0.11). Conclusions— A low-saturated-fat diet introduced in infancy and maintained during the first decade of life is associated with enhanced endothelial function in boys. The effect is explained in part by the diet-induced reduction in serum cholesterol concentration.

Fatty Acid Metabolism in the Liver, Measured by Positron Emission Tomography, Is Increased in Obese Individuals

BACKGROUND & AIMS Hepatic lipotoxicity results from and contributes to obesity-related disorders. It is a challenge to study human metabolism of fatty acids (FAs) in the liver. We combined (11)C-palmitate imaging by positron emission tomography (PET) with compartmental modeling to determine rates of hepatic FA uptake, oxidation, and storage, as well as triglyceride release in pigs and human beings. METHODS Anesthetized pigs underwent (11)C-palmitate PET imaging during fasting (n = 3) or euglycemic hyperinsulinemia (n = 3). Metabolic products of FAs were measured in arterial, portal, and hepatic venous blood. The imaging methodology then was tested in 15 human subjects (8 obese subjects); plasma (11)C-palmitate kinetic analyses were used to quantify systemic and visceral lipolysis. RESULTS In pigs, PET-derived and corresponding measured FA fluxes (FA uptake, esterification, and triglyceride FA release) did not differ and were correlated with each other. In human beings, obese subjects had increased hepatic FA oxidation compared with controls (mean +/- standard error of the mean, 0.16 +/- 0.01 vs 0.08 +/- 0.01 micromol/min/mL; P = .0007); FA uptake and esterification rates did not differ between obese subjects and controls. Liver FA oxidation correlated with plasma insulin levels (r = 0.61, P = .016), adipose tissue (r = 0.58, P = .024), and systemic insulin resistance (r = 0.62, P = .015). Hepatic FA esterification correlated with the systemic release of FA into plasma (r = 0.71, P = .003). CONCLUSIONS PET imaging can be used to measure FA metabolism in the liver. By using this technology, we found that obese individuals have increased hepatic oxidation of FA, in the context of adipose tissue insulin resistance, and increased FA flux from visceral fat. FA flux from visceral fat is proportional with the mass of the corresponding depot.

Effect of Weight Loss on Liver Free Fatty Acid Uptake and Hepatic Insulin Resistance

OBJECTIVE Weight loss has been shown to decrease liver fat content and whole-body insulin resistance. The current study was conducted to investigate the simultaneous effects of rapid weight reduction with a very-low-calorie diet on liver glucose and fatty acid metabolism and liver adiposity. HYPOTHESIS We hypothesized that liver insulin resistance and free fatty acid uptake would decrease after weight loss and that they are associated with reduction of liver fat content. DESIGN Thirty-four healthy obese subjects (body mass index, 33.7 +/- 8.0 kg/m(2)) were studied before and after a very-low-calorie diet for 6 wk. Hepatic glucose uptake and endogenous glucose production were measured with [(18)F]fluorodeoxyglucose during hyperinsulinemic euglycemia and fasting hepatic fatty acid uptake with [(18)F]fluoro-6-thia-heptadecanoic acid and positron emission tomography. Liver volume and fat content were measured using magnetic resonance imaging and spectroscopy. RESULTS Subjects lost weight (11.2 +/- 2.9 kg; P < 0.0001). Liver volume decreased by 11% (P < 0.002), which was partly explained by decreased liver fat content (P < 0.0001). Liver free fatty acid uptake was 26% lower after weight loss (P < 0.003) and correlated with the decrement in liver fat content (r = 0.54; P < 0.03). Hepatic glucose uptake during insulin stimulation was unchanged, but the endogenous glucose production decreased by 40% (P < 0.04), and hepatic insulin resistance by 40% (P < 0.05). CONCLUSIONS The liver responds to a 6-wk period of calorie restriction with a parallel reduction in lipid uptake and storage, accompanied by enhancement of hepatic insulin sensitivity and clearance.

Population-Based Twin Study of the Effects of Migration From Finland to Sweden on Endothelial Function and Intima-Media Thickness

Finnish men have higher coronary heart disease (CHD) mortality than Swedish men do. To assess the impact of migration to a country with lower CHD mortality on subclinical atherosclerosis, we measured early functional and structural atherosclerotic vascular changes in twins discordant for migration from Finland to Sweden. Conventional CHD risk factors, flow-mediated dilatation (FMD) of the brachial artery, carotid intima-media thickness, and carotid artery compliance were measured in 74 male twin pairs (20 monozygous, 54 dizygous), aged 42 to 69 years, in which co-one twin had migrated more than 20 years ago permanently to Sweden. There were no significant differences in CHD risk factors except for diastolic blood pressure and body fat percentage, which were higher in Sweden. In all subjects, mean FMD was non-significantly higher in Sweden (5.7±4.3% vs 4.9±4.2%, P =0.22), but in monozygous twins the difference in FMD was highly significant (7.2±4.4 vs 3.7±2.9%, P =0.003). There was no significant difference in intima-media thickness or carotid artery compliance between Sweden and Finland. We conclude that in Finnish monozygous twins the endothelial function is better among the twins that have migrated to a country with lower CHD prevalence.

Effect of Caloric Restriction on Myocardial Fatty Acid Uptake, Left Ventricular Mass, and Cardiac Work in Obese Adults

Obesity is associated with increased fatty acid uptake in the myocardium, and this may have deleterious effects on cardiac function. The aim of this study was to evaluate how weight loss influences myocardial metabolism and cardiac work in obese adults. Thirty-four obese (mean body mass index 33.7 +/- 0.7 kg/m(2)) but otherwise healthy subjects consumed a very low calorie diet for 6 weeks. Cardiac substrate metabolism and work were measured before and after the diet. Myocardial fatty acid uptake was measured in 18 subjects using fluorine-18-fluoro-6-thia-heptadecanoic acid and positron emission tomography, and myocardial glucose uptake was measured in 16 subjects using fluorine-18-2-fluoro-2-deoxyglucose. Myocardial structure and cardiac function were measured using magnetic resonance imaging. Consumption of the very low calorie diet decreased weight (-11.2 +/- 0.6 kg, p <0.0001). Myocardial fatty acid uptake decreased from 4.2 +/- 0.4 to 2.9 +/- 0.2 micromol/100 g/min (p <0.0001). Myocardial mass decreased by 7% (p <0.005), and cardiac work decreased by 26% (p <0.0001). Whole-body insulin sensitivity increased by 33% (p <0.01), but insulin-stimulated myocardial glucose uptake remained unchanged (p = 0.90). Myocardial triglyceride content decreased by 31% (n = 8, p = 0.076). In conclusion, weight reduction decreases myocardial fatty acid uptake in parallel with myocardial mass and cardiac work. These results show that the increased fatty acid uptake found in the hearts of obese patients can be reversed by weight loss.