McGill HC, McMahan CA, Zieske AW, Malcom GT, Tracy RE, Strong JP. Effect of nonlipid risk factors on atherosclerosis in youth with favorable lipoprotein profile. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Circulation 103, 1546-1550
The strong association between coronary heart disease and dyslipoproteinemia has often overshadowed the effects of the nonlipid risk factors-smoking, hypertension, obesity, and diabetes and impaired glucose tolerance-and even led to questioning the importance of these risk factors in the presence of a favorable lipoprotein profile.
A cooperative multicenter study, the Pathobiological Determinants of Atherosclerosis in Youth (PDAY), examined the relation of the nonlipid risk factors to atherosclerosis in 629 men and 227 women 15 to 34 years of age who died of external causes and who had a favorable lipoprotein profile (non-HDL cholesterol <4.14 mmol/L [<160 mg/dL] and HDL cholesterol >/=0.91 mmol/L [>/=35 mg/dL]). In the abdominal aorta, smokers had more extensive fatty streaks and raised lesions than nonsmokers, and hypertensive blacks had more raised lesions than normotensive blacks. In the right coronary artery, hypertensive blacks had more raised lesions than normotensive blacks, obese men (body mass index >/=30 kg/m(2)) had more extensive fatty streaks and raised lesions than nonobese men, and individuals with impaired glucose intolerance had more extensive fatty streaks. Obese men had more severe lesions (American Heart Association grade 2 through 5) of the left anterior descending coronary artery.
These substantial effects of the nonlipid risk factors on the extent and severity of coronary and aortic atherosclerosis, even in the presence of a favorable lipoprotein profile, support the need to control all cardiovascular risk factors.
"The pathogenesis of early atherosclerosis as identified by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) trial begins with a fatty streak of lipid filled macrophages accumulating in the intima of an artery. Next, it was shown that vascular smooth muscle proliferated and entered the intima forming a fibrous area . A common manifestation of early atherosclerosis in children and teenagers is diffuse thickening of the intima-media space rather than discrete lipid core and fibrous cap formation . "
[Show abstract][Hide abstract] ABSTRACT: Background. Our goal was to compare the carotid intimal-medial thickness (CIMT) of untreated pediatric patients with metabolic syndrome (MS), heterozygous familial hyperlipidemia (heFH), and MS+heFH against one another and against a control group consisting of healthy, normal body habitus children. Methods. Our population consisted of untreated pediatric patients (ages 5-20 yrs) who had CIMT measured in a standardized manner. Results. Our population included 57 with MS, 23 with heFH, and 10 with MS+heFH. The control group consisted of 84 children of the same age range. Mean CIMT for the MS group was 469.8 μ m (SD = 67), 443.8 μ m (SD = 61) for the heFH group, 478.3 μ m (SD = 70) for the MS+heFH group, and 423.2 μ m (SD = 45) for the normal control group. Significance differences between groups occurred for heFH versus MS (P = 0.022), heFH versus control (P = 0.038), MS versus control (P = 9.0E - 10), and MS+heFH versus control (P = 0.003). Analysis showed significant negative correlation between HDL and CIMT (r = -0.32, P = 0.03) but not for LDL, triglycerides, BP, waist circumference, or BMI. Conclusion. For pediatric patients, the thickest CIMT occurred for patients with MS alone or for those with MS+heFH. This indicates that MS, rather than just elevated LDL, accounts for more rapid thickening of CIMT in this population.
"ICAM-1, VCAM-1) that mediate monocyte homing  . In diabetic mouse models, chronic hyperglycemia is strongly associated with the formation of early plaques, termed fatty streaks , and postmortem analysis of young patients and children with type 1 diabetes show enhanced fatty streak formation  , suggesting that hyperglycemia promotes early plaque development. While recent clinical trials (ACCORD, ADVANCE) failed to find a significant effect of stringent glucose control on cardiovascular outcomes in diabetic patients  , these data may result from the timing of glycemic control, as 10 year follow-ups of the DCCT and UKPDS trials found that tight glycemic control early following diagnosis of diabetes significantly decreases cardiovascular events  . "
[Show abstract][Hide abstract] ABSTRACT: Objective
Altered subendothelial matrix composition regulates endothelial dysfunction and early atherosclerotic plaque formation. Hyperglycemia promotes endothelial matrix remodeling associated with multiple microvascular complications of diabetes, but a role for altered matrix composition in diabetic atherogenesis has not been described. Therefore, we sought to characterize the alterations in matrix composition during diabetic atherogenesis using both in vitro and in vivo model systems.
Methods and Results
Streptozotocin-induced diabetes in atherosclerosis-prone ApoE knockout mice promoted transitional matrix expression (fibronectin, thrombospondin-1) and deposition in intima of the aortic arch as determined by qRT-PCR array and immunohistochemistry. Early plaque formation occurs at discrete vascular sites exposed to disturbed blood flow patterns, whereas regions exposed to laminar flow are protected. Consistent with this pattern, hyperglycemia-induced transitional matrix deposition was restricted to regions of disturbed blood flow. Laminar flow significantly blunted high glucose-induced fibronectin expression (mRNA and protein) and fibronectin fibrillogenesis in endothelial cell culture models, whereas high glucose-induced fibronectin deposition was similar between disturbed flow and static conditions.
Taken together, these data demonstrate that flow patterns and hyperglycemia coordinately regulate subendothelial fibronectin deposition during early atherogenesis.
"Taken together, it is suggested that absolutely equal exercise volume without consideration of subject's body weight may explain the current controversy in _ V O 2max enhancement among different exercise intensity groups. Blood lipids are well documented as a contributing factor, leading to the pathogenesis of atherosclerosis, which is the underlying cause of coronary heart disease (McGill et al. 2001), and are known to be favorably affected by endurance exercise training (Leon and Sanchez 2001). We identified that a number of risk factors are unaltered by either highintensity or low-intensity exercise training in the present study. "
[Show abstract][Hide abstract] ABSTRACT: The primary purpose of this study was to investigate the effects of high-intensity exercise training under relatively equal energy expenditure on whole body fat and abdominal fat loss, and cardiorespiratory fitness. Twenty-two untrained middle-aged Korean females were randomized into one of the following groups: control, low-intensity training group (LI), and high-intensity training group (HI). Subjects completed 14 weeks of training at 50% maximal oxygen consumption (LI) or 70% maximal oxygen consumption (HI) with the volume of exercise equated relative to kilograms of body weight. Weekly exercise volumes were 13.5 METs⋅h/week for the first 4 weeks, 18 METs⋅h/week for next 5 weeks, and 22.5 METs⋅h/week for the final 5 weeks. Data were analyzed using 2-way repeated measures ANOVA with post hoc test, using Bonferroni's correction. HI showed significant reductions in fat mass (p < 0.05), total abdominal fat (p < 0.01), and subcutaneous abdominal fat (p < 0.01). LI reduced total abdominal fat (p < 0.05), but there were no other significant changes found in the control or LI groups. Maximal oxygen consumption was enhanced in both HI and LI with no significant group difference. High-density lipoprotein cholesterol increased significantly in HI (p < 0.05). IL-6, C-reactive protein, TNF-α, and other blood lipids were unaltered following training. Results indicate that high-intensity exercise training is more beneficial in whole body and abdominal fat loss; however, cardiorespiratory enhancement shows a dose-response relationship with weekly exercise volume. It is suggested that 14 weeks of aerobic exercise training at either high- or low-intensity is not sufficient enough to induce changes in levels of inflammatory proteins.
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