Arterial stiffness increases with ageing as described a century ago by Bramwell and Hill , although they measured carotid-radial pulse wave velocity: a muscular arterial segment assessment from the upper arm. It is now established that the assessment of the elastic arterial stiffness in middle-aged and older adults strongly predicts cardiovascular events and all-cause mortality [2–4]. Therefore, carotid-femoral pulse wave velocity (cfPWV) is considered the gold standard for assessing arterial stiffness . On the basis of evidence among middle-aged and older adults, interventions aimed at preventing arterial stiffness are currently ongoing or proposed to mitigate stiffness-related disease epidemics [6–8]. Unfortunately, arterial stiffness research as a predictor of diseases among adolescents and young adults lags [4,9]. Several studies conducted among young population have utilized arterial stiffness as a surrogate atherosclerotic cardiovascular outcome, such that hypertension, obesity, hyperglycaemia, insulin resistance and other cardiometabolic diseases predicted higher arterial stiffness [4,9–14]. The paucity of normative longitudinal data based on age, sex, body size and hypertensive state among adolescents and young adults may have limited the clinical utility of arterial stiffness measures in paediatric clinical practice [9,11,12,15–19]. Longitudinal findings from the Avon Longitudinal Study of Parents and Children (ALSPAC) suggest that arterial stiffness, measured with cfPWV, could be an independent predictor of several risk factors for cardiometabolic diseases in a very large cohort of adolescents [20–22]. Extensive details of arterial stiffness assessments, haemodynamics, physics and mechanobiology have been published earlier [5,6,9,23]. This review summarizes recent epidemiological evidence on arterial stiffness usefulness in young population [20–22,24] and proposes future directions.
A BRIEF SYNOPSIS OF ARTERIAL STIFFNESS HAEMODYNAMICS
During cardiac contraction, pressure waves travel along the arterial tree and the speed is measured as pulse wave velocity (PWV). An earlier return of the reflected pulse wave to the proximal aorta increases cardiac afterload. Stiffening increases the power associated with a given flow, which may damage the microcirculation, such as small arteries and arterioles. This damage seems to be more prominent in high-flow organs [1,4,6]. The forward travelling pressure and flow waves are initiated by cardiac contractions, and partial wave reflection occurs when a forward wave encounters regions of impedance mismatch leading to the returned or backward wave. Arterial characteristic impedance is the proportion of a forward traveling pressure to flow wave speed in early systole, that is the change in pressure for a given change in flow, prior to the return of prominent wave reflections. In young healthy adults, low impedance ensures that nominal ventricular ejection produces a low amplitude forward travelling pressure wave moving down the aorta at a relatively low PWV. However, as arteries stiffen with age, impedance and forward traveling pressure increase leading to higher PWV [4,6,7,25].
ARTERIAL STIFFNESS WITH THE RISK OF ELEVATED BLOOD PRESSURE AND HYPERTENSION
The prevalence of age-adjusted elevated blood pressure and hypertension in 1522 U.S. adolescents aged 13–17 years accessed between 2007 and 2010 was 9.5 and 4.6%, respectively . The male to female ratio for diagnosed arterial hypertension in the U.S. adolescent cohort was 3 : 1 . Moreover, the prevalence of elevated systolic blood pressure and hypertension among 3862 British adolescents aged 17.7 years accessed between 2008 and 2010 is 21.3 and 6.3%, respectively . The male to female ratio for elevated SBP in the British cohort at age 17.7 and 24.5 years was 5 : 1 and 3 : 1, respectively . The disparity in the prevalence of elevated blood pressure between the U.S. and British studies is due to the mean ages of study participants, that is 13–17 versus 17.7–24.5 years [20,26]. A recent review reported that the prevalence of primary hypertension among 18-year-old adolescents was 10–11%, but among male adolescents, the prevalence is 16–21% . This increasing prevalence of hypertension in late adolescence and young adulthood and its sequelae, especially among male adolescents, warrants further study [16,27,28]. A systematic review and meta-analysis of prospective studies reported that elevated blood pressure in the young was associated with an intermediate marker of cardiovascular disease, high PWV, in adulthood [odds ratio (OR) 1.83; 95% confidence interval (CI), 1.39–2.40] . However, none of the included longitudinal studies in the meta-analysis had baseline measures of PWV and thus could not examine plausible causal inference (i.e. the direction of the association) . The authors suggested that early life arterial thickening and stiffening may cause elevated blood pressure (reverse causation), but the sequence of events may be less likely at young versus older ages . A cross-sectional evidence from the ENIGMA study conducted in 2005 among 1028 healthy university students in Cambridge and Wales, aged 17–27 years, suggests that arterial stiffness may be an underlying major haemodynamic abnormality for essential hypertension .
Recently, longitudinal evidence from repeated measures of cfPWV in 3862 apparently healthy adolescents revealed that adolescent arterial stiffness may causally precede elevated blood pressure and hypertension in young adulthood  contrary to the systematic review and meta-analysis report . The mean (SD) cfPWV for boys at 17.7 and 24.5 years was 6.03 (0.70) and 6.71 (1.19) m/s, respectively, whilst that of girls was 5.54 (0.62) m/s at 17.7 years and 6.09 (1.01) m/s at 24.5 years (Fig. 1) . The authors found that among boys, a higher cfPWV at 17.7 years predicted elevated SBP and/or hypertension [OR 1.31 (CI 1.02–1.70)] and elevated DBP and/or hypertension [OR 2.18 (CI 1.49–3.19)] at 24.5 years but not among girls [OR 1.09 (CI 0.83–1.42)] and [OR 1.40 (CI 0.91–2.16)], respectively . Adolescents in the highest quartile of cfPWV at 17.7 and 24.5 years had a two-fold increase in SBP and DBP during the 7-year observation period when compared with those at the lower second quartile of cfPWV (Fig. 2) . It is expected that a true risk factor is implicated in the causal path of a disease process. On the contrary, a risk marker is associated with the disease process without being in the causal pathway . Temporal relationship is a critical initial step in establishing causation but not necessarily sufficient; therefore, strong evidence for causal inference must additionally test for the strength of association, consistency, presence of a dose-response relationship and a plausible pathogenic pathway between the cause and effect . Using several advanced statistical models, such as the mixed-effect hierarchical model and cross-lagged autoregressive structural equation models, the ALSPAC study among adolescents reported a plausible temporal causal relationship between arterial stiffness and elevated blood pressure/hypertension, tested the strength of associations, consistency and dose-response relationships (Figs. 1 and 2) . All analyses were controlled for risk factors measured both at baseline and follow-up such as age, sex, low-density lipoprotein cholesterol, insulin, triglyceride, high-sensitivity C-reactive protein, high-density lipoprotein cholesterol, heart rate, glucose, fat mass, lean mass, smoking status, family history of hypertension/diabetes/high cholesterol/vascular disease and moderate to vigorous physical activity.
Arterial stiffness increases with age across the life course, excessive stiffening could lead to early organ dysfunction and damage [4,6,7,9,31,32]. The origin of arterial stiffness in early life remains a huge debate, whether it is vascular structure driven or a consequence of prenatal disorders in either vascular smooth muscle tone or volume expansion [6,33,34]. The genetic contribution to arterial stiffening is moderate with an estimated 40% heritability of high cfPWV . Perinatal sclerotic lesions in foetal arteries have been observed in babies of mothers who are smokers just as telomere length has been suggested to influence intrauterine programming of arterial dysfunction in postnatal life [36,37]. About three decades ago, passive smoking was associated with early arterial damage assessed as dose-related impairment of endothelium-dependent dilatation in healthy young adults . Recently, it was observed in the ALSPAC cohort that smoking exposure from ages 13 through 17 years, even at low levels of less than 20 cigarettes in a lifetime, was associated with higher cfPWV at 17 years of age . Existing background metabolic diseases have been associated with higher arterial stiffness in youths [24,40]. Longitudinal studies among adults have shown that arterial stiffening may also be caused by the combined effect of elevated heart rate and blood pressure due to increased mechanical stress fatigue in the arterial wall [32,41–43]. A high sodium intake has been associated with arterial stiffness, development of extracellular matrix and alteration in secretory properties of vascular smooth muscle cells independent of blood pressure . It was suggested that endothelial cells lining the artery lumen may serve as sensors of modified dietary salt intake for generating signal-transduction events that lead to growth factor production, shear stress modification and potentially arterial stiffness . Safar et al. comprehensively reviewed the plausible causal role of dietary salt intake on arterial stiffness. Over a decade ago, Fernhall et al. , in a review, discussed the origin of arterial function in youth, which might be a window into cardiovascular risk. The present review summarises current evidence, which answers some of Fernhall et al. proposed future research questions among youths.
Elastic artery stiffening results in rapid backflow of blood to the heart, early return of wave reflections, increased pulsatile load and cardiac output. This increased pulsatile power results in hyper-perfusion of high-flow organs causing microvascular damage. Arterial stiffening increases forward pressure waveform amplitude and pulse pressure resulting in elevated systolic pressure and subsequent diastolic dysfunction via concentric left ventricular remodelling and hypertrophy [4,6,7,9,31,32]. In a healthy adolescent and young adult, the highly elastic aorta stores energy during systole, which is released during elastic recoil in diastole. There is a dampening of this elastic recoil when arteries stiffen due to reduced atrioventricular plane displacement [4,6,31]. This may be evident in the recent study wherein participants who were consistently in the highest quartile of cfPWV from adolescence through young adulthood had a two-fold higher SBP and DBP increase over the 7 years when compared with those who had optimal cfPWV . It is thus necessary that future studies investigate whether adolescent arterial stiffness temporally precedes ventricular hypertrophy, and cardiac diastolic and systolic dysfunction in young adulthood, independent of blood pressure and heart rate. Evidence from mouse studies indicates that impairment of elastin expression leads to arterial stiffening and constriction, prior to the increase in blood pressure and that the increase in blood pressure is inversely associated with arterial elastin content [32,45]. Moreover, young participants diagnosed with elastin haploinsufficiency syndrome have been observed to have elevated arterial stiffness before developing hypertension . Consistent with the foregoing, adolescent arterial stiffness may be the ‘egg or cause’ and young adulthood elevated blood pressure/hypertension the ‘chicken or effect’ [20,29,32]. Existing vicious cycle between arterial stiffness and high blood pressure suggests a blood pressure-dependent arterial stiffness. Arterial stiffness in adolescence and young adulthood may also be a consequence of higher blood pressure in childhood [47–49]. However, careful and accurate assessment is warranted to investigate the temporal relationships between arterial stiffness and elevated blood pressure from infancy through young adulthood.
ARTERIAL STIFFNESS WITH THE RISK OF OVERWEIGHT AND OBESITY
The prevalence of adolescent obesity is on the rise , and several efforts targeted at decreasing this trend in the long term have yielded limited success . Among 3862 adolescents from the ALSPAC study, it was reported that boys had a significant increase in overweight and obesity compared with girls during the 7-year observation period . Several studies have reported the inconsistent effects of overweight and obesity on arterial stiffness during adolescence and young adulthood [10,18,52–55]. Although the mechanism through which obesity influences arterial stiffening in early life remains incompletely elucidated, it was postulated that autonomic and metabolic dysfunction may alter sympathovagal balance via effects on arterial smooth muscle . Moreover, vascular adipose and immune cell dysfunction have been associated with obesity-induced arterial stiffness . Studies in animal models have shown that increased obesity in mice fed with a high-fat and high-sucrose diet was associated with stiffer arteries within a month and that arterial stiffening occurred due to activation of inflammatory markers, oxidative stress and reduced bioavailability of nitric oxide . This evidence suggests that obesity may temporally precede arterial stiffness.
However, most human studies that have related measures of obesity with arterial stiffness have used BMI, BMI-Z-scores and percentiles as measures of body composition [10,18]. These measures of body composition do not clearly distinguish the role of fat mass from muscle mass in their relationships with arterial stiffness. Recently, it was reported that cumulative fat mass from age 9 through 17 years directly measured using dual-energy X-ray absorptiometry was associated with higher arterial stiffness at 17 years of age . Similarly, another study in the same population showed that cumulative fat mass from ages 9 through 24 years was associated with higher arterial stiffness at 24 years of age . However, the cumulative fat mass measured from ages 9 through 24 years was not associated with the 7-year increase or progression in arterial stiffness from ages 17 through 24 years . Nonetheless, overweight/obese girls had statistically significantly higher cfPWV both at 17 and 24 years in contrast to normal-weight girls . On the contrary, overweight/obese boys had lower cfPWV at age 24 years in comparison with normal weight males, although not statistically significant . The disparities in the prospective studies [18,47,53,54] suggest that the dynamic changes in fat mass from childhood through young adulthood may not be directly associated with arterial stiffness progression, especially in a healthy young population. There were significant differences in cfPWV values classified based on weight categories across different longitudinal cohorts, that is ALSPAC and Cincinnati Cohort [20,24] (Table 1). These differences may be due to weight classification, that is BMI percentiles versus BMI cut-points, the combination of overweight and obese categories in the ALSPAC cohort in relation to the normal weight and the combination of normal and overweight in the Cincinnati cohort versus obese categories [20,24]. Another important difference between the two studies is that the Cincinnati cohort used the robust measurement of aortic PWV by arterial tonometry (SphygmoCor), while the ALSPAC cohort used the oscillometric cuff derived PWV (Vicorder) [20,24]. In youth, Vicorder aortic PWV values were similar to those obtained by SphygmoCor applanation tonometry with the best agreement between devices obtained in the aortic tree path length . An excellent intra and interobserver repeatability and measurements ease make Vicorder appropriate for large young population studies . Nonetheless, clinical outcome studies that utilized oscillometric aortic PWV measures are limited . The ALSPAC cohort had a longer follow-up period of 7 years in contrast to 5 years in the Cincinnati cohort, although the baseline ages were similar [20,24]. Also, in both longitudinal cohorts, cfPWV was elevated in the overweight and/or obese categories [20,24] (Table 1).
TABLE 1 -
Comparison of carotid-femoral pulse wave velocity values according to weight categories across longitudinal cohorts
||ALSPAC (UK) cohort 
||Cincinnati (US) cohort 
||Age in years
||cfPWV (m/s) Mean (SD)
||Age in years
||cfPWV (m/s) Mean (SD)
cfPWV, carotid-femoral pulse wave velocity.
Understanding the complex and possibly vascular adaptive relationships between obesity and arterial stiffness warrants temporal longitudinal studies . The first-ever temporal longitudinal report revealed that higher cfPWV in adolescence independently predicted a nearly 20% increased risk of either total or trunk fat mass overweight/obesity in young adulthood . Moreover, the cross-lagged temporal findings showed that bidirectional relationships exist between arterial stiffness and total or trunk fat mass (Fig. 3), although the relationship was two-fold stronger when total or trunk fat mass predicted higher cfPWV . Obesity is a high-flow condition that promotes arterial remodelling via a decrease in elastic fibre thickness with a resultant elevation in stress and strain . The increased strain leads to higher collagen deposit, higher wall stiffness and raised cfPWV . It was also reported that the 7-year increase in cfPWV was paradoxically associated with the 7-year decrease in total or trunk fat mass . This finding suggests that arterial stiffness may play a role in fat metabolism and deposit since increased arterial stiffness leads to high-flow low-resistance microvascular organ damage in the liver and pancreas, but further longitudinal, pathological and mechanistic studies are needed.
ARTERIAL STIFFNESS WITH THE RISK OF HYPERGLYCAEMIA AND INSULIN RESISTANCE
The precursors of young-onset type 2 diabetes, that is type 2 diabetes diagnosed before the age of 40 years, are elevated insulin resistance, hyperglycaemia and altered metabolic milieu [59–61]. The global prevalence of young-onset type 2 diabetes is rising, and recent evidence among adolescents diagnosed with the disease reported several early organ damages within a mean time of 13.3 ± 1.8 years [61,62]. In addition, recent randomized controlled trials, metformin monotherapy and/or lifestyle modification have been unsuccessful in treating young-onset type 2 diabetes, warranting further research on ways to reduce the risk in early life [63,64]. Established precursors and consequences of young-onset type 2 diabetes are high blood pressure, dyslipidaemia and family history of diabetes [61–64]. Longitudinal studies have reported higher cfPWV in adolescents with type 1 and 2 diabetes [24,65,66]. Therefore, identifying other preventable risk factors of young-onset type 2 diabetes may help ameliorate the incidence of the disease, particularly among adolescents and young adults [61,62].
About a year and a half ago, it was reported among 14 159 healthy Chinese adults aged 48.3 ± 12.0 years, followed up for 3.72 years, that higher arterial stiffness may temporal precede higher fasting blood glucose and could be causally associated with incident type 2 diabetes . In the same Chinese cohort, among 11 156 middle-aged adults, it was recently shown that arterial stiffness had a better predictive ability than hypertension in predicting type 2 diabetes and that the pathological path between arterial stiffness and diabetes may not be modified by the ageing process of inflammation and oxidation . Earlier, in a Swedish elderly cohort of 2450 individuals aged 71.9 ± 5.6 years, followed up for 4.43 ± 1.40 years, it was observed that increased cfPWV was associated with increased incidence of diabetes, independent of other risk factors . These adult studies suggest that arterial stiffness may be a novel risk factor for incident type 2 diabetes mellitus [67–69]. However, whether arterial stiffness could be a potential risk factor for young-onset type 2 diabetes or its precursor among adolescents and young adults is unknown. Emerging evidence among 3862 healthy adolescents from the ALSPAC study suggests that arterial stiffness may predict hyperinsulinemia in young adulthood, after a 7-year follow-up . Further extensive investigation of the same cohort employing advanced statistical models revealed that arterial stiffness may temporally precede insulin resistance and hyperinsulinemia (Fig. 3) . Due to few incidences of young-onset type 2 diabetes in the cohort, the authors could not examine the temporal causal association between arterial stiffness and incident young-onset type 2 diabetes among adolescents [21,22].
In contrast to the Chinese adult study , arterial stiffness among adolescents does not appear to precede hyperglycaemia in the causal path , probably because the adult study employed an assessment of arterial stiffness (brachial-ankle PWV) that includes a considerable muscular component, which may limit the specificity of the measurement. Moreover, the adult study analyses did not account for participants’ insulin levels despite evidence that insulin at physiologic concentrations acutely diminishes arterial stiffness greater than those controlling peripheral vascular resistance [67,70]. The study that purportedly demonstrated that insulin decreases large artery stiffness used augmentation index as a measure of aortic stiffness . Augmentation index is related to the propagation of the reflected waves and is not an accurate index of arterial stiffness, depending mainly on heart rate and peripheral resistance, and slightly on arterial stiffness [6,9]. As central arterial stiffness predicts hard cardiovascular events, it may be clinically useful in additionally predicting early risk of young-onset type 2 diabetes (hyperinsulinemia and insulin resistance) [2–4,21,22]. Considering that previous randomized controlled trials on the treatment of young-onset type 2 diabetes have been unsuccessful [63,64], these emerging longitudinal evidence among adolescents [21,22] and adults  suggest that future intervention aimed at treating young-onset type 2 diabetes may consider a concurrent reduction of arterial stiffness in addition to diabetes therapy . Evidence from the ALSPAC study revealed that irrespective of sex, cfPWV and fasting insulin levels were significantly higher among overweight/obese and elevated blood pressure/hypertensive youths, both at 17 and 24 years of age . Moreover, arterial stiffness progression (predictor) was close to having a statistically significant association with the 7-year increase in fasting insulin (outcome), among overweight/obese participants who made up one-fifth of the adolescent population . These findings suggest that arterial stiffness, obesity and insulin resistance may be inextricably linked in the development of type 2 diabetes mellitus, with arterial stiffness potentially initiating the disease cascade [6,20,22,67,71,72]. Increased proinflammatory cytokines especially from higher visceral adiposity have been associated with altered insulin metabolic signalling, insulin-mediated nitric oxide production and arterial stiffening [72,73]. Nonetheless, accounting for high-sensitivity C reactive protein, an inflammatory marker, in the analyses did not alter the temporal relationships between arterial stiffness and insulin resistance [20–22]. Of note, the effect of smoking status, physical activity levels, sedentary behaviour, family history of diabetes, dyslipidaemia and cardiovascular diseases on the temporal associations were not significant, probably because most adolescents were apparently healthy . Arterial stiffness preceding hyperinsulinemia and insulin resistance (Fig. 3) implicates insulin response rather than production. Therefore, the known effects of aortic stiffness on microvascular reactivity in the periphery may explain the association of aortic stiffness with subsequent insulin resistance/diabetes [4,22,67]. Nonetheless, the pathological mechanism by which arterial stiffness may independently contribute to metabolic alterations warrants further research.
ARTERIAL STIFFNESS WITH THE RISK OF DYSLIPIDAEMIA
Longitudinal studies relating dyslipidaemia with worsening arterial stiffness among youth are few, and the relationships attenuate after controlling for conventional risk factors [6,24,74,75]. It is postulated that subendothelial lipid deposit, increased atheroma deposit and lipid peroxidation are potential pathophysiological mechanisms that support lipid-induced atherosclerosis, which could simultaneously occur with arterial stiffening depending on the arterial site [6,76]. There is no evidence of the longitudinal associations of repeated measures of cfPWV and repeated lipid measures, and whether lipid alteration temporally precedes arterial stiffness was largely unknown. Again, the ALSPAC study involving 3862 adolescents followed up for 7 years bridged the gap in knowledge by reporting that temporal or bidirectional associations of either low-density lipoprotein cholesterol and triglyceride with arterial stiffness may not exist, particularly among apparently healthy youths . These temporal causal findings may explain why clinical trials aimed at reducing arterial stiffness from lipid-lowering drugs have been mildly effective, nearly 6.8% reduction [6,77,78]. Nonetheless, it seems likely that adolescent arterial stiffness may temporally precede decreased high-density lipoprotein cholesterol in young adulthood in the causal path . It was reported that a 1 m/s rise in cfPWV during adolescence was independently associated with a –0.3 mmol decrease in high-density lipoprotein cholesterol (P = 0.051) in young adulthood after accounting for cardiometabolic and lifestyle factors . Further longitudinal analysis revealed that the 7-year increase in arterial stiffness was directly associated with a 7-year increase in triglyceride, although not in the causal path. Taken together, it appears that arterial stiffness progression may be associated with reduced high-density lipoprotein cholesterol and elevated triglyceride, but the mechanism by which arterial stiffness alters lipid metabolism remains uncertain.
ARTERIAL STIFFNESS, OBESITY, HYPERTENSION AND INSULIN RESISTANCE
Higher arterial stiffness has been reported among youths with obesity, hypertension, insulin resistance and diabetes mellitus [10,14,24,40,49,70,72,73,79–81]. Decreased physical activity, obesity genes, intrauterine epigenetics, environmental toxins and high fat and fructose diets lead to insulin resistance, obesity, hypertension and arterial dysfunction, suggesting a vicious cycle throughout the lifespan [6,10,52,56,71,72]. Arterial stiffness is driven by a complex interaction of endocrine factors, cytokines, vascular cellular components, extracellular matrix, perivascular adipose tissue and immune cells within the arterial tree [4,56,71,72,79]. Diet-induced obesity and insulin resistance create conditions for impaired endothelial nitric oxide synthase activation, vascular cell-specific mineralocorticoid and insulin receptor activation, increased aldosterone plasma level and decreased nitric oxide bioavailability leading to increased vascular permeability and inflammation, leukocyte adhesion, increased vascular constriction, tissue remodelling and fibrosis [56,71,72,79].
Emerging epidemiological and prospective studies among middle-aged adults consistently report that arterial stiffness may temporally precede the development of diabetes mellitus in the causal path [67–69]. The most recent of these studies, published 2 weeks ago, concluded that arterial stiffness showed a better predictive ability than hypertension in predicting incident type 2 diabetes mellitus . Individuals with the isolated systolic, isolated diastolic, high systolic and diastolic, controlled and uncontrolled hypertensive individuals, the combination of hypertension and elevated arterial stiffness were observed to be at a higher risk of diabetes than other groups . Despite limited clinical events such as incident type 2 diabetes mellitus among population-based youths, the observation that arterial stiffness precedes hypertension and metabolic derangement such as insulin resistance among mostly normal-weight adolescents and young adults may be clinically relevant [20,22]. It is known that age explains most of the variance in models associating cfPWV with risk factors, but this variance also accounts for structural wear and tear, elastin fragmentation and increased collagen deposition . Emerging studies in young and middle-aged populations suggest a knowledge gap in risk factors that should be intensely investigated in light of the burden of disease potentially attributable to arterial stiffening [4,6,20,22,67,68,72].
CLINICAL UTILITY OF ARTERIAL STIFFNESS IN PAEDIATRICS AND FUTURE DIRECTION
Arterial stiffness diminishes the impedance between normal gradient compliant elastic and stiff muscular arteries [4,7]. This results in an increased transmitted pulsatile power and load into the conduit vessels, small arteries and microcirculation, leading to organ damage and remodelling [4,7]. Emerging longitudinal observations among adolescents and young adults suggest that cfPWV may be a useful early indicator of cardiometabolic derangement, enabling paediatricians and healthcare providers to encourage youth to adopt early lifestyle modifications, before the onset of severe target organs damage to the heart, liver, pancreas, brain, kidney and so on [3–5,7,20,22,82,83]. Due to lack of data to assess normal versus abnormal cfPWV values, the 2017 American Academy of Pediatrics Clinical Practice Guidelines did not recommend the routine assessment of cfPWV in youth with suspected hypertension . The recent availability of normative longitudinal data on cfPWV based on age, sex, body size and hypertensive state among 3862 adolescents and young adults [20,22] from the ALSPAC study and 448 adolescents and young Cincinnati cohort  (Table 1 and Figs. 1 and 2) could be useful in updating existing reference values for cfPWV in healthy adolescents and clinical guidelines, such as the European Society of Hypertension/European Society of Cardiology guidelines for the management of arterial hypertension and the American Academy of Pediatrics Clinical Practice Guidelines [9,12,15–17,19,83–87]. However, normative cfPWV data among adolescents from diverse ethnic or racial backgrounds are still limited [20,24,88].
Studies examining arterial stiffness temporal progression with early organ damage such as the brain, heart, liver, pancreas and kidney are warranted among adolescents and young adults, as temporal associations have been demonstrated in adult studies [4,6,7,9,16,89]. It is also pertinent to determine the primary risk factor for worsening arterial stiffness in an apparently healthy adolescents, apart from age and sex. Temporal longitudinal studies of arterial stiffness progression in relation to cardiometabolic alterations are needed in a multiethnic adolescent population because arterial stiffness has been strongly associated with ethnicity . Future basic and clinical studies are required to examine how secreted metabolites released by adipose tissues among normal-weight and obese individuals explain the contribution of excess adiposity to insulin resistance and pathogenesis of hypertension and arterial stiffening in the young population [6,51,71,72]. Several dietary and exercise clinical trials have failed to lower arterial stiffness in the young population [90–92]. A recent meta-analysis on the acute effect of exercise on arterial stiffness in healthy participants also reported a null exercise effect on cfPWV after 24 h . Recently, a randomized, placebo-controlled, double-blind clinical trial that examined the effect of angiotensin-converting enzyme inhibitors and/or statins on vascular phenotypes among adolescents with type 1 diabetes reported no effect on cfPWV . Nonetheless, arterial stiffness has emerged as a major novel risk factor for the development of hypertension, total and truncal obesity, hyperinsulinemia, insulin resistance, type 2 diabetes, and possibly dyslipidaemia among apparently healthy adolescents, young adults [6,20,22,29,89], (Fig. 3) and middle-aged adults [67,68]; therefore, new strategies  and interventional trials to mitigate arterial stiffness in youth are urgently needed [95–98]. Assessment of arterial stiffening can be conducted in the paediatric clinic with relative ease compared with an electrocardiogram [7,9,17,82,83], and these observational studies [20–22,29] provide arterial stiffness normative data that could be utilized in patient management . There is now a strong theoretical argument to include arterial stiffness as a trigger to initiate antihypertensive therapy in paediatric and young adult populations [19,89]. Lastly, arterial stiffness may not be considered only as hypertension-induced target organ damage, or signs of early vascular ageing [9,16,17,19,83,89] but may be clinically defined and treated as a potential cause of elevated blood pressure/hypertension and altered cardiometabolic functions in youths having no prior disease risks.
Higher arterial stiffness in adolescence may potentially be a novel risk factor for young adulthood hypertensive and metabolic disease, which is now being established among adults [6,22,67–69]. Higher arterial stiffness in early life may result from maternal smoking habits, early life smoking patterns, high salt intake, genetic programming, obesity, elevated blood pressure and other poor cardiometabolic and lifestyle factors [4,6,34,56,71,72]. This review summarizes recent advances in the study of arterial stiffness in youth [14,20,22,24,34,40] and proposes future directions. It must be noted that high-calorie intake and physical inactivity remain the primary cause of metabolic disorders in our current society [10,51,56,71,72]. The observation that arterial stiffening precedes metabolic alteration or cholesterol metabolism [20,22] could indicate arterial stiffening as an early marker of a series of biological alterations finally leading to disease formation such as type 2 diabetes mellitus [4,67,68]. Thus, the underlying mechanisms for which arterial stiffness contributes to metabolic disorder in youth require urgent clinical studies and basic research.
Dr Agbaje was funded by the Jenny and Antti Wihuri Foundation (Grant no: 00180006); the North Savo regional and central Finnish Cultural Foundation (Grants no: 65191835 and 00200150); the Orion Research Foundation sr; the Aarne Koskelo Foundation; the Antti and Tyyne Soininen Foundation; the Paulo Foundation; the Paavo Nurmi Foundation; the Yrjö Jahnsson Foundation (Grant no: 20217390), the Finnish Foundation for Cardiovascular Research (Grant no: 220021). Open access publication was partly funded by the University of Eastern Finland.
Conflicts of interest
There are no conflicts of interest.
1. Bramwell JC, Hill AV. Velocity of transmission of the pulse-wave and elasticity of arteries. Lancet
2. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness. A systematic review and meta-analysis. J Am Coll Cardiol
3. Ben-Shlomo Y, Spears M, Boustred C, May M, Anderson SG, Benjamin EJ, et al. Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects. J Am Coll Cardiol
4. Chirinos JA, Segers P, Hughes T, Townsend R. Large-artery stiffness in health and disease: JACC state-of-the-art review. J Am Coll Cardiol
5. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J
6. Boutouyrie P, Chowienczyk P, Humphrey JD, Mitchell GF. Arterial stiffness and cardiovascular risk in hypertension. Circ Res
7. Mitchell GF. Arterial stiffness in aging: does it have a place in clinical practice? Hypertension
8. Laurent S, Chatellier G, Azizi M, Calvet D, Choukroun G, Danchin N, et al. SPARTE Study: normalization of arterial stiffness and cardiovascular events in patients with hypertension at medium to very high risk. Hypertension
9. Townsend RR, Wilkinson IB, Schiffrin EL, Avolio AP, Chirinos JA, Cockcroft R, et al. Recommendations for improving and standardizing vascular research on arterial stiffness: a scientific statement from the American Heart Association. Hypertension
10. Cote AT, Phillips AA, Harris KC, Sandor GGS, Panagiotopoulos C, Devlin AM. Obesity and arterial stiffness in children: systematic review and meta-analysis. Arterioscler Thromb Vasc Biol
11. Mendizábal B, Urbina EM. Subclinical atherosclerosis in youth: relation to obesity, insulin resistance, and polycystic ovary syndrome. J Pediatr
12. Climie RE, Park C, Avolio A, Mynard JP, Kruger R, Bruno RM. Vascular ageing in youth: a call to action. Hear Lung Circ
13. Agbaje AO, Barker AR, Tuomainen TP. Cardiorespiratory fitness, fat mass, and cardiometabolic health with endothelial function, arterial elasticity, and stiffness. Med Sci Sport Exerc
14. Urbina EM, Isom S, Bell RA, Bowlby DA, D’Agostino R Jr, Daniels SR, et al. Burden of cardiovascular risk factors over time and arterial stiffness in youth with Type 1 diabetes mellitus: the SEARCH for Diabetes in Youth Study. J Am Heart Assoc
15. Mattace-Raso FUS, Hofman A, Verwoert GC, Wittemana JCM, Wilkinson I, Cockcroft J, et al. Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: ‘Establishing normal and reference values.’. Eur Heart J
16. Khoury M, Urbina EM. Hypertension in adolescents: diagnosis, treatment, and implications. Lancet Child Adolesc Heal
2021; 5:357–366. doi:10.1016/S2352-4642(20)30344-8.
17. Lurbe E, Agabiti-Rosei E, Cruickshank JK, Dominiczak A, Erdine S, Hirth A, et al. 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents. J Hypertens
18. Stoner L, Kucharska-Newton A, Meyer ML. Cardiometabolic health and carotid-femoral pulse wave velocity in children: a systematic review and meta-regression. J Pediatr
19. Flynn JT, Kaelber DC, Baker-Smith CM, Blowey D, Carroll AE, Daniels SR, et al. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics
20. Agbaje AO, Barker AR, Tuomainen TP. Effects of arterial stiffness and carotid intima- media thickness progression on the risk of overweight/obesity and elevated blood pressure/hypertension: a cross-lagged cohort study. Hypertension
21. Agbaje AO, Barker AR, Tuomainen TP. Differing relations of arterial stiffness and carotid intima-media thickness in adolescence with metabolic risks in young adulthood: The ALSPAC Study. Circulation
2021; 144: (Suppl 1): A13236.
22. Agbaje AO, Barker AR, Mitchell GF, Tuomainen TP. Effect of arterial stiffness and carotid intima-media thickness progression on the risk of dysglycemia, insulin resistance, and dyslipidaemia: a temporal causal longitudinal study. Hypertension
23. Segers P, Rietzschel ER, Chirinos JA. How to measure arterial stiffness in humans. Arterioscler Thromb Vasc Biol
24. Ryder JR, Northrop E, Rudser KD, Kelly AS, Gao Z, Khoury PR, et al. Accelerated early vascular aging among adolescents with obesity and/or type 2 diabetes mellitus. J Am Heart Assoc
25. Segers P, O’Rourke MF, Parker K, Westerhof N, Hughes A. Towards a consensus on the understanding and analysis of the pulse waveform: results from the 2016 Workshop on Arterial Hemodynamics: past, present and future. Artery Res
26. Hardy ST, Sakhuja S, Jaeger BC, Urbina EM, Suglia SF, Feig DI, Muntner P. Trends in blood pressure and hypertension among US children and adolescents, 1999-2018. JAMA Netw Open
27. Litwin M, Feber J. Origins of primary hypertension in children: early vascular or biological aging? Hypertension
28. Yang L, Magnussen CG, Yang L, Bovet P, Xi B. Elevated blood pressure in childhood or adolescence and cardiovascular outcomes in adulthood: a systematic review. Hypertension
29. McEniery CM, Yasmin, Wallace S, Maki-Petaja K, McDonnell B, Sharman JE, et al. Increased stroke volume and aortic stiffness contribute to isolated systolic hypertension in young adults
30. Franklin SS. Arterial stiffness and hypertension: a two-way street? Hypertension
31. Safar ME, Asmar R, Benetos A, Blacher J, Boutouyrie P, Lacolley P, et al. Interaction between hypertension and arterial stiffness an expert reappraisal. Hypertension
32. Mitchell GF. Arterial stiffness and hypertension: chicken or egg? Hypertension
33. Iurciuc S, Cimpean AM, Mitu F, Heredea R, Iurciuc M. Vascular aging and subclinical atherosclerosis: why such a ‘never ending’ and challenging story in cardiology? Clin Interv Aging
34. Fernhall B, Agiovlasitis S. Arterial function in youth: window into cardiovascular risk. J Appl Physiol
35. Mitchell GF, DeStefano AL, Larson MG, Benjamin EJ, Chen MH, Vasan RS, et al. Heritability and a genome-wide linkage scan for arterial stiffness, wave reflection, and mean arterial pressure: the Framingham Heart Study. Circulation
36. Nilsson PM, Boutouyrie P, Cunha P, Kotsis V, Narkiewicz K, Parati G, et al. Early vascular ageing in translation: from laboratory investigations to clinical applications in cardiovascular prevention. J Hypertens
37. Hodis S, Zamir M. Mechanical events within the arterial wall: the dynamic context for elastin fatigue. J Biomech
38. Celermajer DS, Adams MR, Clarkson P, Robinson J, McCredie R, Donald A, Deanfield JE. Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults
. N Engl J Med
39. Charakida M, Georgiopoulos G, Dangardt F, Chiesa ST, Hughes AD, Rapala A, et al. Early vascular damage from smoking and alcohol in teenage years: the ALSPAC study. Eur Heart J
40. Shah AS, El ghormli L, Gidding SS, Hughan KS, Levitt Katz LE, Koren D, et al. Longitudinal changes in vascular stiffness and heart rate variability among young adults
with youth-onset type 2 diabetes: results from the follow-up observational treatment options for type 2 diabetes in adolescents and youth (TODAY) study. Acta Diabetol
41. Ashor AW, Lara J, Siervo M, Celis-Morales C, Mathers JC. Effects of exercise modalities on arterial stiffness and wave reflection: a systematic review and meta-analysis of randomized controlled trials. PLoS One
42. Millasseau SC, Stewart AD, Patel SJ, Redwood SR, Chowienczyk PJ. Evaluation of carotid-femoral pulse wave velocity: influence of timing algorithm and heart rate. Hypertension
43. Tan I, Butlin M, Spronck B, Xiao H, Avolio A. Effect of heart rate on arterial stiffness as assessed by pulse wave velocity. Curr Hypertens Rev
44. Safar ME, Temmar M, Kakou A, Lacolley P, Thornton SN. Sodium intake and vascular stiffness in hypertension. Hypertension
45. Le VP, Knutsen RH, Mecham RP, Wagenseil JE. Decreased aortic diameter and compliance precedes blood pressure increases in postnatal development of elastin-insufficient mice. Am J Physiol Heart Circ Physiol
46. Salaymeh KJ, Banerjee A. Evaluation of arterial stiffness in children with williams syndrome: does it play a role in evolving hypertension? Am Heart J
47. Agbaje AO, Barker AR, Tuomainen TP. A 15-year cumulative high exposure to lean mass and blood pressure but not fat mass predicts the 7-year change in carotid-femoral pulse wave velocity and carotid intima-media thickness: the ALSPAC study. Circulation
2021; 143: (Suppl 1): A080.
48. Kollios K, Nika T, Kotsis V, Chrysaidou K, Antza C, Stabouli S. Arterial stiffness in children and adolescents with masked and sustained hypertension. J Hum Hypertens
49. Li S, Chen W, Srinivasan SR, Berenson GS. Childhood blood pressure as a predictor of arterial stiffness in young adults
50. Bentham J, Di Cesare M, Bilano V, et al. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults. Lancet
51. Hall ME, Cohen JB, Ard JD, Egan BM, Hall JE, Lavie CJ, et al. Weight-loss strategies for prevention and treatment of hypertension: a scientific statement from the American Heart Association. Hypertension
52. Cote AT, Harris KC, Panagiotopoulos C, Sandor GG, Devlin AM. Childhood obesity and cardiovascular dysfunction. J Am Coll Cardiol
53. Dangardt F, Charakida M, Georgiopoulos G, Chiesa ST, Rapala A, Wade KH, et al. Association between fat mass through adolescence and arterial stiffness: a population-based study from The Avon Longitudinal Study of Parents and Children. Lancet Child Adolesc Heal
54. Agbaje AO, Barker AR, Tuomainen TP. Longitudinal associations of fat mass, lean mass, body mass index and blood pressure from childhood through young adulthood with carotid-femoral pulse wave velocity and carotid intima-media thickness at age 24.5 years. J Am Coll Cardiol
2021; 77: (18 Suppl 1): 1490.
55. Hudson LD, Rapala A, Khan T, Williams B, Viner RM. Evidence for contemporary arterial stiffening in obese children and adolescents using pulse wave velocity: a systematic review and meta-analysis. Atherosclerosis
56. Aroor AR, Jia G, Sowers JR. Cellular mechanisms underlying obesity-induced arterial stiffness. Am J Physiol Regul Integr Comp Physiol
57. Weisbrod RM, Shiang T, Al Sayah L, Fry JL, Bajpai S, Reinhart-King CA, et al. Arterial stiffening precedes systolic hypertension in diet-induced obesity. Hypertension
58. Kracht D, Shroff R, Baig S, Doyon A, Jacobi C, Zeller R, et al. Validating a new oscillometric device for aortic pulse wave velocity measurements in children and adolescents. Am J Hypertens
59. American Diabetes Association. 2. Classification and diagnosis of diabetes: Standards of Medical Care in Diabetes-2020. Diabetes Care
2020; 43: (Suppl 1): S14–S31.
60. Dabelea D, Stafford JM, Mayer-Davis EJ, D’Agostino R, Dolan L, Imperatore G, et al. Association of type 1 diabetes vs type 2 diabetes diagnosed during childhood and adolescence with complications during teenage years and young adulthood. JAMA
61. Chan JCN, Lim LL, Wareham NJ, Shaw JE, Orchard TJ, Zhang P, et al. The Lancet Commission on diabetes: using data to transform diabetes care and patient lives. Lancet
62. TODAY Study Group. Long-term complications in youth-onset Type 2 diabetes. N Engl J Med
63. TODAY Study Group. Postintervention effects of varying treatment arms on glycemic failure and β-cell function in the TODAY Trial. Diabetes Care
64. TODAY Study Group. Effects of metformin, metformin plus rosiglitazone, and metformin plus lifestyle on insulin sensitivity and -βcell function in TODAY. Diabetes Care
65. Bjornstad P, Pyle L, Nguyen N, Snell-Bergeon JK, Bishop FK, Wadwa RP, Maahs DM. Achieving International Society for Pediatric and Adolescent Diabetes and American Diabetes Association clinical guidelines offers cardiorenal protection for youth with type 1 diabetes. Pediatr Diabetes
66. Dabelea D, Talton JW, D’Agostino R, Wadwa RP, Urbina EM, Dolan LM, et al. Cardiovascular risk factors are associated with increased arterial stiffness in youth with type 1 diabetes: the search CVD study. Diabetes Care
67. Zheng M, Zhang X, Chen S, Song Y, Zhao Q, Gao X, Wu S. Arterial stiffness preceding diabetes: a longitudinal study. Circ Res
68. Tian X, Zuo Y, Chen S, Zhang Y, Zhang X, Xu Q, et al. Hypertension, arterial stiffness, and diabetes: a prospective cohort study. Hypertension
69. Muhammad IF, Borné Y, Östling G, Kennbäck C, Gottsäter M, Persson M, et al. Arterial stiffness and incidence of diabetes: a population-based cohort study. Diabetes Care
70. Westerbacka J, Yki-Järvinen H. Arterial stiffness and insulin resistance. Semin Vasc Med
71. Koenen M, Hill MA, Cohen P, Sowers JR. Obesity, adipose tissue and vascular dysfunction. Circ Res
72. Hill MA, Yang Y, Zhang L, Sun Z, Jia G, Parrish AR, et al. Insulin resistance, cardiovascular stiffening and cardiovascular disease. Metabolism
73. Jia G, Sowers JR. Hypertension in diabetes: an update of basic mechanisms and clinical disease. Hypertension
74. Koivistoinen T, Hutri-Kähönen N, Juonala M, Kööbi T, Aatola H, Lehtimäki T, et al. Apolipoprotein B is related to arterial pulse wave velocity in young adults
: the Cardiovascular Risk in Young Finns Study. Atherosclerosis
75. Aatola H, Hutri-Kähönen N, Juonala M, Viikari JS, Hulkkonen J, Laitinen T, et al. Lifetime risk factors and arterial pulse wave velocity in adulthood: the cardiovascular risk in young finns study. Hypertension
76. Lakatta EG, Wang M, Najjar SS. Arterial aging and subclinical arterial disease are fundamentally intertwined at macroscopic and molecular levels. Med Clin North Am
77. Upala S, Wirunsawanya K, Jaruvongvanich V, Sanguankeo A. Effects of statin therapy on arterial stiffness: a systematic review and meta-analysis of randomized controlled trial. Int J Cardiol
78. D’elia L, La Fata E, Iannuzzi A, Rubba PO. Effect of statin therapy on pulse wave velocity: a meta-analysis of randomized controlled trials. Clin Exp Hypertens
79. Prenner SB, Chirinos JA. Arterial stiffness in diabetes mellitus. Atherosclerosis
80. Urbina EM, Gao Z, Khoury PR, Martin LJ, Dolan LM. Insulin resistance and arterial stiffness in healthy adolescents and young adults
81. Urbina EM, Kimball TR, Khoury PR, Daniels SR, Dolan LM. Increased arterial stiffness is found in adolescents with obesity or obesity-related type 2 diabetes mellitus. J Hypertens
82. Wilkinson IB, Mäki-Petäjä KM, Mitchell GF. Uses of arterial stiffness in clinical practice. Arterioscler Thromb Vasc Biol
83. Urbina EM, Williams RV, Alpert BS, Collins RT, Daniels SR, Hayman L, et al. Noninvasive assessment of subclinical atherosclerosis in children and adolescents: recommendations for standard assessment for clinical research: a scientific statement from the american heart association. Hypertension
84. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH). Eur Heart J
85. Reusz GS, Cseprekal O, Temmar M, Kis E, Cherif AB, Thaleb A, et al. Reference values of pulse wave velocity in healthy children and teenagers. Hypertension
86. Thurn D, Doyon A, Sözeri B, Bayazit AK, Canpolat N, Duzova A, et al. Aortic pulse wave velocity in healthy children and adolescents: reference values for the vicorder device and modifying factors. Am J Hypertens
87. Sarkola T, Manlhiot C, Slorach C, Bradley TJ, Hui W, Mertens L, et al. Evolution of the arterial structure and function from infancy to adolescence is related to anthropometric and blood pressure changes. Arterioscler Thromb Vasc Biol
88. Schutte AE, Kruger R, Gafane-Matemane LF, Breet Y, Strauss-Kruger M, Cruickshank JK. Ethnicity and arterial stiffness. Arterioscler Thromb Vasc Biol
89. Hope KD, Zachariah JP. Predictors and consequences of pediatric hypertension: have advanced echocardiography and vascular testing arrived? Curr Hypertens Rep
90. Davis CL, Litwin SE, Pollock NK, Waller JL, Zhu H, Dong Y, et al. Exercise effects on arterial stiffness and heart health in children with excess weight: the SMART RCT. Int J Obes
91. Rajakumar K, Moore CG, Khalid AT, Vallejo AN, Virji MA, Holick MF, et al. Effect of vitamin D3 supplementation on vascular and metabolic health of vitamin D-deficient overweight and obese children: a randomized clinical trial. Am J Clin Nutr
92. McNarry MA, Lester L, Ellins EA, Halcox JP, Davies G, Winn CON, et al. Asthma and high-intensity interval training have no effect on clustered cardiometabolic risk or arterial stiffness in adolescents. Eur J Appl Physiol
93. Saz-Lara A, Cavero-Redondo I, Álvarez-Bueno C, Notario-Pacheco B, Ruiz-Grao MC, Martínez-Vizcaíno V. The acute effect of exercise on arterial stiffness in healthy subjects: a meta-analysis. J Clin Med
94. Chiesa ST, Marcovecchio ML, Benitez-Aguirre P, Cameron FJ, Craig ME, Couper JJ, et al. Vascular effects of ACE (angiotensin-converting enzyme) inhibitors and statins in adolescents with Type 1 diabetes. Hypertension
95. Zachariah JP. Causal mechanisms in adolescent arterial stiffness (Internet). https://clinicaltrials.gov/ct2/show/NCT04128969
[Accessed 5 April 2022]
96. Kruger R, Monyeki MA, Schutte AE, Smith W, Mels CMC, Kruger HS, et al. The exercise, arterial modulation and nutrition in youth South Africa study (ExAMIN youth SA). Front Pediatr
97. Sacre JW, Jennings GLR, Kingwell BA. Exercise and dietary influences on arterial stiffness in cardiometabolic disease. Hypertension
98. Lau CWZ, Hamers AJP, Rathod KS, Shabbir A, Cooper J, Primus CP, et al. Randomised, double-blind, placebo-controlled clinical trial investigating the effects of inorganic nitrate in hypertension-induced target organ damage: protocol of the NITRATE-TOD study in the UK. BMJ Open