Traditional cardiovascular risk factors

The role of hypercholesterolemia, and particularly high LDL cholesterol levels (164–166) (but also hypertriglyceridemia (167) and low HDL cholesterol levels (168)), hypertension (165,169), obesity (170), and male gender (165) are widely accepted risk factors for coronary heart disease (171).

Autopsy study revealed these classical cardiovascular risk factors to be strongly associated in cumulative manner with the extent of fatty streaks and fibrous plaques already in children and young adults (57). These risk factors in childhood also predicts higher levels of cardiovascular risk in adulthood: higher levels of LDL cholesterol, triglycerides, SBP, and body mass index (BMI) was associated with higher cIMT thickness in adult men (24-39 years), and a higher number of these risk factors (assessed at 12-18 years of age) was associated with increased cIMT in both genders in a Finnish population sample (172).

Similar results, in which an increase in LDL cholesterol and BMI in childhood predicts increased cIMT in adulthood, was reported in two different studies in the USA (173,174).

Clustering of these risk factors in childhood also predicted stiffer arteries in adulthood (175).

Childhood cholesterol levels, BP levels, and BMI also tends to track into adulthood (176,177), where their role as cardiovascular risk factors are well known (171).

2.6.1.1 Overweight and obesity

In almost every study listed in Tables 3-6, obesity has been linked to higher arterial stiffness as measured by PWV (8) and PCA (12), and poorer endothelial function as measured by FMD (178) and RH-PAT (179) and higher cIMT (180) in childhood. Obesity is associated with arterial stiffness and endothelial dysfunction also in adults (181).

The link between obesity and arterial stiffness and endothelial dysfunction could be due to the obesity-associated elevation of other classical cardiovascular risk factors, increased

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oxidative stress, low-grade inflammation, and insulin resistance, all which have an adverse effect on arterial elasticity and endothelial function (182).

2.6.1.2 Hypercholesterolemia and dyslipidemia

As measured by PWV, higher arterial stiffness was seen in those children with higher total cholesterol, LDL cholesterol, or triglyceride levels, and lower HDL cholesterol levels (10,183). Also one study using a PCA device showed higher arterial stiffness in those children with lower HDL cholesterol or higher triglycerides (12) (Table 3 and 5). In addition, higher cIMT was associated with higher levels of triglyceride, LDL cholesterol, and lower levels of HDL cholesterol in children (11,180,184).

Associations of poorer endothelial function and an increase in total and LDL cholesterol levels is seen in adults (185). Some studies reported in Tables 4 and 5 found no association s with the lipid profile and measures of endothelial function in healthy (11,186,187) or obese (187,188). Another study however showed inverse association with endothelial function and total and LDL cholesterol as measured with FMD and these associations remained after adjusted with age, HDL cholesterol,SBP,gender,BMI, and brachial artery diameter (189). In addition, when classified as normal or as having endothelial dysfunction using a measure of reactive hyperemia due occlusion of radial and ulnar artery measured with laser Doppler from the finger, higher triglycerides were seen in those with endothelial dysfunction, but also a difference in adiposity was present (190). Only low levels of HDL was associated in obese persons with decreased FMD (191). Another study also showed an inverse association of hypercholesterolemia and FMD in obese (180). These discrepancies, where some studies found statistically significant associations, could be methodological as the assessments of endothelial function differed and in one study (192) the measurement time after occlusion was too short (189). However, in most studies with significant associations between dyslipidemia and endothelial dysfunction, the findings were seen only in obese and thus be additive and thus more measurable. Also lack of measurements of lipoprotein (a) could be explanation for the lack of significant findings in some studies, as higher levels of lipoprotein(a) was reported to be associated with poorer endothelial function in children (193). In addition, in children with familial hypercholesterolemia, endothelial function is worse, but of the subgroups of lipids, only lipoprotein(a) (but not LDL,HDL, or triglycerides) was associated inversely with FMD (194). Hypercholesterolemia and lipoprotein(a) is suggested to have complementary effects on endothelial dysfunction (195).

One explanation regarding the harmfulness of hypercholesterolemia (and in particularly high LDL cholesterol) could be its tendency to become oxidized, causing arterial stiffness by damaging elastin (196) and endothelial dysfunction by affecting l-arginine (197) uptake and downregulating endothelial nitric oxide synthase (eNOS) expression (34,198).

2.6.1.3 Elevated blood pressure

In children, arterial stiffness as measured with PWV was independently associated with higher SBP, diastolic blood pressure (DBP), and mean BP (10,183,199). Also one study with PCA device showed higher arterial stiffness in those with hypertension (12) (Table 3,5 and 6).

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Studies on children and adolescents showing an association of endothelial dysfunction with BP have been scarce. Only one study reported SBP and DBP correlating inversely with FMD and only in obese boys (191), while in other studies no results were reported or no correlations were found in healthy (186,200) or obese children (187,188) (Table 4 and 5).

Higher cIMT is associated with higher levels of SBP and DBP in obese children (184).

High BP and arterial stiffness have bidirectional mechanical and functional influences on each other (201). Arterial stiffness has been shown to predict hypertension (202), and hypertension has been shown to accelerate arterial stiffness in adults (203). BP is a strong determinant of FMD in adults (204) and elevated BP in adolescent boys predicted impaired brachial FMD in 21 years later in adulthood (205). These findings suggest that hypertension causes measurable changes in endothelial function relatively slowly.

2.6.1.4 Gender

The role of female gender as protective in preventing coronary heart diseases is well known (206). This effect lasts up to menopause, after which secretion of estrogen declines (207). The protective value of female sex-hormones is seen also for stiffening of arteries. Arteries are more distensible in younger women than in men, but after menopause the opposite findings are seen (208). Endothelial function is also better in women, but the age-related decrease accelerates after 45 years and endothelial function is worse in females than males after 70 years of age (209).

Similar findings are also seen in children, where higher arterial stiffness was seen in prepubertal girls than boys, but the opposite was seen in the postpubertal state (accompanied with an increase in estradiol and progesterone in females and testosterone in males) (210). Another study found no sex differences between prepubertal boys and girls, but higher arterial stiffness in postpubertal boys than girls (211). Endothelial function also improves as puberty advances in both genders, indicating the effect of sex hormones (212).

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velocity CF Peripheral and central SBP ↓ Obesity ↑ Age groups are range or means (~, rounded value; ±, standard deviation). ↓/↑, lower/higher arterial compliance with an increase in variables listed before sign. CF, carotid-femoral; TRI, triglycerides; hs-CRP, high sensitivity c-reactive protein; DBP/MAP/SBP, diastolic/mean/systolic blood pressure; BMI, body mass index; WC, waist circumference; WHR,waist-to-height-ratio; HOMA, homeostatic model assessment of insulin resistance; CA, local carotid artery.

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