Jaakko Hartiala

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.

Cardiac Positron Emission Tomography/Computed Tomography Imaging Accurately Detects Anatomically and Functionally Significant Coronary Artery Disease

Background— Computed tomography (CT) is increasingly used to detect coronary artery disease, but the evaluation of stenoses is often uncertain. Perfusion imaging has an established role in detecting ischemia and guiding therapy. Hybrid positron emission tomography (PET)/CT allows combination angiography and perfusion imaging in short, quantitative, low-radiation-dose protocols. Methods and Results— We enrolled 107 patients with an intermediate (30% to 70%) pretest likelihood of coronary artery disease. All patients underwent PET/CT (quantitative PET with 15O-water and CT angiography), and the results were compared with the gold standard, invasive angiography, including measurement of fractional flow reserve when appropriate. Although PET and CT angiography alone both demonstrated 97% negative predictive value, CT angiography alone was suboptimal in assessing the severity of stenosis (positive predictive value, 81%). Perfusion imaging alone could not always separate microvascular disease from epicardial stenoses, but hybrid PET/CT significantly improved this accuracy to 98%. The radiation dose of the combined PET and CT protocols was 9.3 mSv (86 patients) with prospective triggering and 21.8 mSv (21 patients) with spiral CT. Conclusion— Cardiac hybrid PET/CT imaging allows accurate noninvasive detection of coronary artery disease in a symptomatic population. The method is feasible and can be performed routinely with <10 mSv in most patients. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00627172.

Weight Reduction With Very-Low-Caloric Diet and Endothelial Function in Overweight Adults: Role of Plasma Glucose

Objective—Obesity is associated with endothelial dysfunction that may contribute to the development of atherosclerosis. We studied whether weight reduction improves endothelial function in overweight individuals. Methods and Results—Flow-mediated endothelium-dependent vasodilation of the brachial artery was measured in 67 adults (age: 46±7 years, body mass index: 35.2±5.4 kg/m2) before and after a 6-week weight reduction program induced by very-low-calorie diet (daily energy: 580 kcal/2.3 MJ). Caloric restriction reduced body weight from 101±18 to 90±17 kg. Flow-mediated vasodilation increased from 5.5%±3.7 to 8.8%±3.7% (P <0.0001). Nitrate-mediated vasodilation was not significantly affected. The improvement in flow-mediated dilation was associated with the reduction in plasma glucose concentration (P =0.0003). This relationship was independent of changes in weight, serum lipids, oxidized LDL, C-reactive protein, adiponectin, blood pressure, and insulin. Conclusions—Weight reduction with very-low-calorie diet improves flow-mediated vasodilation in obese individuals. This improvement is related to the reduction in plasma glucose concentration. These observations suggest that changes in glucose metabolism may determine endothelial vasodilatory function in obesity.

Quantification of mitral regurgitation by velocity-encoded cine nuclear magnetic resonance imaging☆

OBJECTIVES The feasibility of velocity-encoded cine nuclear magnetic resonance (NMR) imaging to measure regurgitant volume and regurgitant fraction in patients with mitral regurgitation was evaluated. BACKGROUND Velocity-encoded cine NMR imaging has been reported to provide accurate measurement of the volume of blood flow in the ascending aorta and through the mitral annulus. Therefore, we hypothesized that the difference between mitral inflow and aortic systolic flow provides the regurgitant volume in the setting of mitral regurgitation. METHODS Using velocity-encoded cine NMR imaging at a magnet field strength of 1.5 T and color Doppler echocardiography, 19 patients with isolated mitral regurgitation and 10 normal subjects were studied. Velocity-encoded cine NMR images were acquired in the short-axis plane of the ascending aorta and from the short-axis plane of the left ventricle at the level of the mitral annulus. Two independent observers measured the ascending aortic flow volume and left ventricular inflow volume to calculate the regurgitant volume as the difference between left ventricular inflow volume and aortic flow volume, and the regurgitant fraction was calculated. Using accepted criteria of color flow Doppler imaging and spectral analysis, the severity of mitral regurgitation was qualitatively graded as mild, moderate or severe and compared with regurgitant volume and regurgitant fraction, as determined by velocity-encoded cine NMR imaging. RESULTS In normal subjects the regurgitant volume was -6 +/- 345 ml/min (mean +/- SD). In patients with mild, moderate and severe mitral regurgitation, the regurgitant volume was 156 +/- 203, 1,384 +/- 437 and 4,763 +/- 2,449 ml/min, respectively. In normal subjects the regurgitant fraction was 0.7 +/- 6.1%. In patients with mild, moderate and severe mitral regurgitation, the regurgitant fraction was 3.1 +/- 3.4%, 24.5 +/- 8.9% and 48.6 +/- 7.6%, respectively. The regurgitant fraction correlated well with the echocardiographic severity of mitral regurgitation (r = 0.87). Interobserver reproducibilities for regurgitant volume and regurgitant fraction were excellent (r = 0.99, SEE = 238 ml; r = 0.98, SEE = 4.1%, respectively). CONCLUSIONS These findings suggest that velocity-encoded NMR imaging can be used to estimate regurgitant volume and regurgitant fraction in patients with mitral regurgitation and can discriminate patients with moderate or severe mitral regurgitation from normal subjects and patients with mild regurgitation. It may be useful for monitoring the effect of therapy intended to reduce the severity of mitral regurgitation.

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.

Constantly low HDL-cholesterol concentration relates to endothelial dysfunction and increased in vivo LDL-oxidation in healthy young men

To test the hypothesis that low HDL-C concentration interferes with vascular endothelial function and lipoprotein oxidation, we measured endothelium-dependent flow mediated dilatation (FMD, %) of the brachial artery in young men (n=20) classified prospectively into two groups on basis of having either low or high HDL-C concentration over the past 2 years. As an estimate of in vivo low-density lipoprotein oxidation (ox-LDL), we measured LDL diene conjugation. FMD was present in the group with high HDL-C concentration, but impaired in the group with low HDL-C (5.5+/-3.2 vs 0.2+/-1.2%, P<0. 001). The group with high HDL-C level had significantly lower levels of ox-LDL compared to low HDL-C group (18.0+/-1.8 vs 22.9+/-4.4, P</=0.01). In all subjects, FMD correlated with HDL-C (r=0.59, P=0. 006), HDL(2)-C (r=0.62, P=0.004) and ox-LDL (r=-0.56, P=0.013) but not with HDL(3)-C (r=0.16, P=0.52). We conclude that constantly low HDL-C concentration is related with endothelial dysfunction and increased oxidative stress in healthy young men, consistent with the idea that HDL particles may protect endothelium and inhibit the oxidation of LDL. These findings may offer insight into increased atherosclerosis associated with low HDL-C levels.

Velocity-encoded cine MRI in the evaluation of left ventricular diastolic function: measurement of mitral valve and pulmonary vein flow velocities and flow volume across the mitral valve.

Left ventricular diastolic function has been evaluated by means of analysis of the flow pattern through the mitral valve. Velocity-encoded cine magnetic resonance imaging (VEC-MR) is a new method for characterizing flow patterns in the heart. The feasibility of using VEC-MR to measure early diastolic (E) and atrial systolic (A) peak flow velocities and E/A ratios in the mitral inflow, as well as systolic (X), early diastolic (Y), and atrial systolic (Z) peak flow velocities and X/Y ratios in the pulmonary vein, was evaluated in 10 normal volunteers. The VEC-MR-derived velocities and indexes were compared with Doppler-derived results. Volumetric flow across the mitral valve was also used to measure stroke volume, cardiac output, and the left atrial contribution of left ventricular filling. VEC-MR yielded lower peak velocities than Doppler echocardiography. The velocities of the two measurements showed a significant linear correlation (Doppler E velocity = 1.30 x VEC-MR + 1.6 cm/sec, r = 0.68; Doppler A velocity = 1.83 x VEC-MR - 5.2 cm/sec, r = 0.83; and Doppler X velocity = 0.45 x VEC-MR + 0.09 cm/sec, r = 0.74). Consequently the E/A and X/Y ratios measured by these two methods showed statistically significant linear correlations with r values of 0.94 and 0.83. The volume of blood flow across the mitral valve measured by VEC-MR (5610 +/- 620 ml/min) was not statistically different from the cardiac output measured from the ascending aorta by VEC-MR (5670 +/- 590 ml/min) or by left ventricular cine magnetic resonance imaging (5440 +/- 614 ml/min). The left atrial contribution to left ventricular filling was 25.9 +/- 7.5%. Our results indicate that VEC-MR can be used not only for evaluation of left ventricular diastolic filling from the mitral valve and pulmonary vein flow velocities but also for quantitative measurement of the volume of blood flow across the mitral valve.

Increased Arterial Intima-Media Thickness and In Vivo LDL Oxidation in Young Men With Borderline Hypertension

We used borderline hypertension as a model for prehypertension to examine the early influences of elevated blood pressure on subclinical atherosclerosis, lipoprotein oxidation, and cardiac adaptation. Healthy men (age 37±4 years) were classified prospectively into 2 groups on the basis of having either borderline hypertension (systolic 130 to 140 mm Hg or diastolic 85 to 89 mm Hg, n=16) or normal (<130/85 mm Hg, n=22) blood pressure values during the previous 2 years. The groups were matched for age, body size, and serum cholesterol levels. High-resolution ultrasound was used to measure intima-media thickness (IMT) of the carotid and brachial arteries, cardiac dimensions, and brachial artery endothelial function. Baseline low-density lipoprotein (LDL)-diene conjugation was measured as an estimate of in vivo LDL oxidation (ox-LDL). Compared with normotensive controls, men with borderline hypertension had higher IMT of the carotid artery (0.58±0.06 versus 0.75±0.07 mm, P <0.001) and IMT of the brachial artery (0.45±0.05 versus 0.57±0.07 mm, P <0.001), and increased levels of ox-LDL (29±9 versus 47±17 mol/L, P <0.001), but similar endothelial function. Left ventricular mass was similar in both groups, but there were significant differences in left ventricular geometry. In multivariate analyses, the predictors of carotid IMT were 24-hour systolic blood pressure (P <0.001) and ox-LDL (P =0.10). The current study demonstrates evidence of increased subclinical atherosclerosis and ox-LDL in borderline hypertension. These results are consistent with the idea that enhanced ox-LDL may be one of the pathophysiological events related to development of atherosclerosis in men with borderline elevated blood pressure.

Large-Artery Elastic Properties in Young Men Relationships to Serum Lipoproteins and Oxidized Low-Density Lipoproteins

Measures of arterial elasticity have been proposed as surrogate markers for asymptomatic atherosclerosis. We investigated the relations of serum lipoproteins, oxidized low-density lipoprotein (ox-LDL), and familial hypercholesterolemia (FH) to arterial elasticity among young men. As a marker of arterial elasticity we measured compliance in the thoracic aorta by using magnetic resonance imaging and in the common carotid artery by using ultrasound. LDL diene conjugation was used as a marker of ox-LDL. In study I, 25 healthy men (aged 29 to 39) were classified into 2 extreme groups according to previously measured high-density lipoprotein cholesterol to total cholesterol ratio (HDL-C/TC ratio). In study II, the healthy men were used as controls for 10 age matched asymptomatic patients with FH. In healthy men, the group with low HDL-C/TC ratio had decreased carotid artery compliance (2. 3+/-0.4% versus 1.9+/-0.5%/10 mm Hg, P=0.034). In univariate analysis, the compliance of the carotid artery associated with ox-LDL (r =-0.49, P=0.016) and HDL-C/TC ratio (r=0.41, P=0.040). In multivariate regression analyses, ox-LDL was the only independent determinant for compliance of the carotid artery (P=0.016). Aortic elasticity was not related to standard lipid variables, but the compliance of the ascending aorta associated with ox-LDL (r=-0.44, P=0.030). In FH patients, arterial elasticity was similar to that in controls. We conclude that elasticity of the common carotid artery is affected by serum lipid profile in young men. The current study demonstrates for the first time an in vivo association between ox-LDL and arterial elasticity suggesting that oxidative modification of LDL may play a role in the alteration of arterial wall elastic properties.

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.