EDITORIAL COMMENT
Metabolic SyndromeIntima-Media Thickness and Beyond*
Beatrice A. Golomb, MD, PhD*
Department of Medicine, University of California–San Diego School of Medicine, La Jolla, California
* Reprint requests and correspondence: Dr. Beatrice A. Golomb, UCSD School of Medicine, Department of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0995 (Email: bgolomb{at}ucsd.edu).
Key Words: atherosclerosis • ultrasound • pre-clinical disease • abdominal aorta • IMT
The paper by Dawson et al. (1) in this issue of the Journal asks: what factors predict or drive the early phases of atherosclerosis, in adolescence and early adulthood, as indexed by aortic intima-media thickness (aIMT) and carotid intima-media thickness (cIMT)? It uses data from 635 members of the Muscatine Offspring Study cohort to do so. And it leads to an important conclusion.
Metabolic syndrome factors (MSF) predict elevated aIMT and cIMT in adolescence (age 11 to 17 years) and young adulthood (age 18 to 34 years). Not all potential risk factors were evaluated: so-called emerging risk factors were absent from consideration (2). In fact, MSF constituted many of the variables assessed (age, sex, and smoking were also measured; among adolescents, smoking was rare and low volume).
With this proviso, in adolescents, adjusting for age, sex, and height, aIMT was linked to triglycerides, systolic and diastolic blood pressure (BP), body mass index (BMI), and waist/hip ratio (WHR); cIMT was linked to systolic BP, BMI, and WHR plus pulse pressure, and heart rate. In young adults, aIMT was linked to those 5 predictors from adolescence, plus high-density lipoprotein (HDL) cholesterol and pulse pressure. The cIMT was linked to triglycerides, BP, BMI, WHR, hemoglobin A1C, and also total and low-density lipoprotein (LDL) cholesterol. High-sensitivity C-reactive protein, an inflammatory marker linked to MSF, was not assessed (3).
In multivariable models adjusting for predictors simultaneously, not unexpectedly, fewer of these (collinear) variables were retained. Which variables were preserved, among such correlated variables, may depend on details of how the manual stepwise regression was performed, but here comprised BMI and/or WHR for all assessments, and variably systolic blood pressure, diastolic blood pressure, or total cholesterol. The finding that MSF are predictors of early atherosclerosis even in youth (whereas LDL cholesterol is not), although not surprising, is nonetheless disquieting in light of the explosion of metabolic syndrome in childhood and afterward (4).
The investigators showed that aIMT (especially in adolescents) and cIMT (especially in young adults) correlate to the PDAY (Pathobiological Determinants of Atherosclerosis in Youth) score, a coronary risk score devised using coronary artery and aortic findings on autopsy (age 15 to 34 years) (5). Both PDAY and IMT look at lesions not at events, and predictors similarly emphasize MSF (plus age, sex, and smoking) (5), so an association is practically foreordained. The investigators use the correlation, nonetheless, to infer that aIMT and cIMT might substitute for risk factors in predicting clinical end points (1). However, the data are not suited to determination of whether either or both IMTs add appreciably to prediction for events. That must be separately studied.
Several questions pertain:
1. Are these data sufficient to establish the suite of risk factors for early IMT elevation? No, of course; it is unlikely that any single study will be. Many nontraditional risk factors have been presumptively linked to IMT in childhood and early adulthood that were not available for consideration, ranging from hyperhomocysteinemia (6,7) and lipoprotein(a) (6), to auto-exhaust (6), growth hormone deficiency (8), and shift work (young adults) (9). Future studies should expand the field of inquiry, including factors potentially proximal to MSF, such as environmental obesogens (10) and pre-natal deprivations (11,12).
2. How should the information be used? Suppose IMT were proved to augment risk prediction; at what risk level would intervention be merited? And with what intervention? Should detection of lesions in adolescence consign a child to a lifetime of drugs? Even among adults, those with a long expected time horizon to events have shown no trend to benefit with the mainstay of coronary prevention, lipid treatment, if outcomes that balance risks and benefits to the patient are considered—all-cause mortality and all-cause serious morbidity (indexed by the available proxy, all-cause serious adverse events) (AFCAPS [Air Force/Texas Coronary Atherosclerosis Prevention Study]) (13,14). Is there reason to suppose that children will fare better? Long-term trials showing benefit in excess of risk should be a necessary pre-condition to broad pharmaceutical recommendations in childhood. Recent randomized trial findings suggesting potential adverse influences of interventions on sleep (15), energy (and interest in activity) (16), and glycemia (17,18)—with prospects for metabolic syndrome implications—only magnify the need for long-term data firmly documenting predominance of benefit before interventions are warranted.
What, then, of lifestyle recommendations? Recent dietary recommendations for lipid management in children, although observed to take on urgency precisely because of the epidemic of metabolic syndrome (19), contravene randomized trial findings on how best to mitigate MSF. (They therefore contravene approaches to best mitigate the factors that the Dawson et al. [1] study suggests predict atherosclerotic risk in young age.) Guidelines advise restricting fat (19), but the randomized A-to-Z trial (20) found that a high-fat, high-protein diet significantly improved BMI, HDL, triglycerides, and systolic and diastolic BP over a low fat diet. (The A-to-Z study was not conducted in children, but the metabolic principles are expected to be similar, and no contrary data support a different approach in childhood.) These metabolic benefits occurred in the absence of lower calorie intake or higher energy expenditure.
Of importance, with the "favorable" diet, LDL trended higher while the total/HDL ratio benefited (20). This is relevant because analyses show that the total/HDL ratio bears the full power of the basic lipid profile in cardiac risk prediction; LDL confers no added prognostic benefit (21). Therefore, others have emphasized that the total/HDL ratio rather than LDL should be the focus of lipid recommendations (21,22). Framingham (adults) and PDAY (children) coronary risk prediction scores implicitly recognize this by including total and HDL cholesterol (or, equivalently, non-HDL and HDL) but not LDL cholesterol in calculating cardiac risk (5,23). Total/HDL but not LDL cholesterol predict cardiovascular risk throughout the lifespan (24–26). The A-to-Z study illustrates that lipid guidelines focused on LDL cholesterol—rather than the evidence-supported total/HDL cholesterol ratio—can impel recommendations (here, for macronutrient intake patterns) that, relative to alternate approaches, may foster MSF and possibly promote cardiovascular risk (per current evidence and risk prediction models).
3. Finally, what do the demonstrated associations of risk factors to early IMT elevations really mean? Even in young life, correlation need not imply causation. More primary factors might drive MSF and atherosclerosis in tandem (with or without MSF also mediating). Oxidative stress represents one candidate precursor, powerfully linked to MSF, potentially causally (27,28)—and in turn linked not just to heart disease (29) but to the panoply of conditions to which metabolic syndrome and diabetes are connected—such as depression (30), fatty liver (31), cancer (32), and cognitive loss (33). There are other such precursors deserving richer discussion than is possible here. In the context of oxidative stress, it bears note that total and LDL cholesterol did not emerge as IMT predictors until young adulthood (and then only for cIMT) (1), suggesting that it is not a most proximal cause. Because LDL cholesterol transports key antioxidants (34–36), one might question whether LDL may increase as an adaptive consequence of other causal factors—with or without its own causal implications.
I respectfully invoke Golomb's Law of biology, which avers that everything in biology is more complicated than one thinks it is, even taking into account Golomb's Law. In the present case, having established that MSF predict IMT in early life, it remains to fully define the forces that propel MSF—past merely calories ingested and expended. We must understand the battalion of influences that drive the scourge of metabolic syndrome—in childhood, before, and beyond—the better to battle them.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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