Author + information
- Harvey S. Hecht, MD⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Harvey S. Hecht, Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1030, New York, New York 10029-6574
The occurrence of atherosclerosis at an early age has long been the subject of curiosity and wonder. Isn't it remarkable that 65 of 140 combat soldiers who died as a result of injuries sustained in World War I had increased coronary atherosclerotic plaques at a mean age of 27.7 years (1)? How interesting is it that grossly visible lesions not causing obstruction were present in 35% of 300 Korean War fatalities at an average of 22.1 years of age, with 39% having 10% to 90% stenosis, 3% total occlusion, and only 23% free of grossly visible coronary lesions (2)! This curiosity quickly dissipates despite confirmation by subsequent landmark studies (3,4) and evidence that favorable risk factor profiles early in life are associated with better outcomes (5,6). Attention is quickly turned to the detection and treatment of atherosclerosis in adults, at which point our best efforts produce only a 30% reduction in events compared with placebo in the primary prevention population (7).
Although dissatisfied with this inadequate event reduction, the cardiology community has been reluctant to seek earlier risk stratification and intervention for several reasons. First, because an event has not yet occurred, the cardiologist believes that there still exists an ample window of opportunity to lower low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) and institute beneficial lifestyle changes. Second, there is great reluctance to implement aggressive evaluation and treatment of children and adolescents for whom the specter of potential lifelong statin treatment and drastic lifestyle changes appears daunting. Third, there is no consensus regarding the appropriate risk stratification tool for this age group. Finally, there have been no data supporting the effect of treating childhood/adolescent risk factors on adult events.
However, there have been several studies linking childhood risk factors to subclinical atherosclerosis. In the Muscatine study (8) of 346 men and 379 women 33 to 42 years of age, multivariable analysis using measurements performed at 8 to 11 years of age identified total cholesterol as a significant risk factor for increased carotid intima-media thickness (CIMT) in men (odds ratio: 1.47) and women (odds ratio: 1.71). The Cardiovascular Risk in Young Finns Study (9) evaluated 2,229 white adults 24 to 39 years of age who were examined at 3 to 18 years of age and underwent CIMT 21 years later. In age- and sex-adjusted multivariable models, CIMT in adulthood was significantly associated with childhood LDL-C levels (p = 0.001), systolic BP (SBP) (p < 0.001), body mass index (p = 0.007), and smoking (p = 0.02) as well as with a number of risk factors (p < 0.001 for both men and women) and remained significant after adjustment for contemporaneous risk variables. The Bogalusa Heart Study (10) of 486 subjects who underwent CIMT at 25 to 37 years of age after initial entry at 4 to 17 years of age reported odds ratios for the highest versus lower 3 quartiles of CIMT of 1.42 for childhood LDL-C and 1.25 for childhood body mass index. In 3 population-based, prospective cohort studies (11) of 1,711 adolescents 12 to 18 years of age who were remeasured as young adults at 29 to 39 years of age, adolescent dyslipidemia status was more strongly associated with high CIMT in adulthood than a change in dyslipidemia status. Using a different modality, the Muscatine study (12) evaluated 384 subjects who had coronary risk factors measured at a mean age of 15 years and coronary artery calcium scanning (CACS) at a mean age of 33 years; coronary artery calcium (CAC) prevalence was 31% in men and 19% in women. The odds ratios for CAC in men and women were, respectively, 6.4 and 13.6 for the highest decile of body mass index, 6.4 and 6.4 for the highest decile of SBP, and 4.3 and 4.7 for the lowest decile of high-density lipoprotein cholesterol.
In this issue of the Journal, Hartiala et al. (13) add significantly to the subclinical atherosclerosis literature. The authors performed CACS in 589 patients, 40 to 46 years of age, from the Cardiovascular Risk in Young Finns Study. Risk factor levels were measured at 12 to 18 years of age and 27 years later at the time of the CACS. Calcified plaque was noted in 19.2%; men had twice the prevalence of women (27.9% vs. 12.2%), as would be expected in a younger population. Levels of traditional risk factors, including age, SBP, total cholesterol, and LDL-C in adolescence, were higher in those with CAC than those without CAC. In adulthood, SBP, total cholesterol, diastolic BP, and pack-years of smoking were higher in patients with CAC. Most importantly, adolescence LDL-C and SBP predicted CAC in adulthood independently of their interim changes, with multivariable odds ratios of 1.34 (p = 0.02) and 1.38 (p = 0.01), for 1-SD increase in adolescence LDL-C and SBP, individually and 3.5 (p = 0.007) for their combination. They concluded that “adolescence risk factor levels play an important role in the pathogenesis of CHD.”
The identification of adolescent lipid and BP abnormalities as the most important predictors of the extent of subclinical atherosclerosis 20 years later, irrespective of their changes over the intervening time period, is somewhat counterintuitive and implies that a tipping point has been triggered at a very early age after which atherosclerosis is more likely to develop. Support for this concept may be provided by tracking correlation coefficients in the range of only 0.4 for cholesterol and BP from 5 to 10 years of age to 20 years later (14); their persistence as adult risk factors is far from certain. Obesity tracks best, with 84% of those with a body mass index in the 95th to 99th percentile range and 100% above the 99th as children continuing as obese adults (14).
It is also important to acknowledge that a fundamental biological truth still eludes our best efforts at discovery. Although risk factors increase the likelihood of disease development and the absence thereof renders disease development less likely on a population basis, the relationship breaks down when applied to the individual patient in whom “all bets are off.” The determinants of susceptibility to risk factors are unknown and may yet be the greatest contribution of the as-yet underperforming field of sophisticated genetic mapping. Fortunately, in the meantime, subclinical atherosclerosis imaging tells us who is susceptible and therefore requires treatment, even if it cannot provide the reason for the susceptibility.
The issues raised by the Hartiala et al. study (13) are at least as intriguing as the findings.
The use of CAC rather than events is reasonable because there are unequivocal data supporting CAC as the most powerful risk stratifier (15), much more so than CIMT. Moreover, the study is neither sufficiently powered nor of long enough duration to allow for clinical outcomes. Nonetheless, critics of subclinical atherosclerosis imaging are likely to object to the use of a surrogate rather than a clinical endpoint.
Are Risk Factors Enough?
A convincing theoretical argument against risk factor–based risk stratification in adults is their relatively equal distribution in those in whom clinical disease does and does not develop. The theory is borne out in reality by the absolutely consistent demonstration of the superiority of CAC-based prognostication to risk factors; CAC is atherosclerosis itself, not merely a risk factor for the disease (15). Because there is no reason to suspect a different pattern in adolescents, are all adolescents with abnormal LDL-C and BP to be treated similarly or is further risk stratification needed to determine the nature and aggressiveness of the treatment? The adult cardiology community has not yet decided whether a subclinical atherosclerosis–based algorithm or a treat-all philosophy without further risk stratification is the most cost-effective; this has not even been discussed in the child and adolescent population.
Even if further risk stratification were desired, the choice of modality is far from clear. Certainly, CAC and coronary computed tomography angiography noncalcified plaque evaluation has no role in this younger population. CIMT is the most feasible but is still troubled by a lack of consensus for study acquisition, inadequate training, considerably poorer risk stratification potency than CAC, and relative lack of data in the child and adolescent population. As 3-dimensional carotid ultrasound evolves, it may provide a more potent tool, but it is still in its infancy. Endothelial function has been evaluated in children (16), but clinical utility has not been demonstrated for any population.
Measurement of risk factors in children is valuable only if beneficial therapeutic recommendations are implemented. In 2011, the National Institutes of Health (NIH)–sponsored Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents (14) recommended that all children should undergo cholesterol screening once between 9 and 11 years of age and once between 17 to 21 years of age; for patients for whom lifestyle changes fail and who require lipid-lowering medications, pharmacological treatment should be considered at 10 years of age. BP should be measured in all children annually between 3 and 18 years of age with drug therapy as dictated by BP levels. Although only a small percentage of children will require medication, this number is likely to increase with the current explosion of obesity.
It is reasonable to assume that NIH guidelines–directed risk factor measurement is honored much more in the breach than in the observance; the screening as well as the therapeutic recommendations are difficult to implement in an overburdened pediatric office setting. Moreover, fears have been raised about an avalanche of statin prescriptions in this young population, particularly in the absence of safety data for their prolonged administration, and, more importantly, absence of beneficial outcome data. Fortunately, the guidelines represent a triumph of common sense over an absolute requirement for large-scale randomized clinical outcome trials, which would be nearly impossible in the childhood and adolescent population.
The extent of benefit from early LDL-C lowering may be greater than anticipated. Ference (17), analyzing data from >1 million patients, used 9 single nucleotide polymorphisms from 6 genes associated with lower LDL-C as a proxy for a treatment that lowers LDL-C beginning at birth to simulate a “natural” randomized, controlled trial. All were associated with a consistent 54% reduction in the risk of a coronary event for each 1-mmol/l (38.7 mg/dl) lower lifetime exposure to LDL-C.
Primordial Versus Primary Prevention
If risk factors in childhood and adolescence are the most powerful determinants of atherosclerosis, future research must focus on preventing the development of risk factors (primordial prevention) rather than on the treatment of the risk factors (primary prevention). “Indeed, childhood must be a focus for primordial prevention research. Unless the spread of risk factors is stemmed at this early age, the world faces an epidemic of cardiovascular disease” (18). The extraordinary projections of the Ference study (17) are based on normalizing LDL-C at birth (primordial prevention) as opposed to treating already established risk factors in childhood and adolescence.
Studies further cementing the link between early risk factors and later disease, similar to the present study by Hartiala et al. (13), are to be encouraged and taken seriously. Until effective genetic manipulation at birth is a reality (if ever), implementation of the NIH guidelines offers the best hope for a pervasive change in the continued epidemic of coronary artery disease, which will be further accelerated by the frightening increase in childhood obesity. It is incumbent on society to reallocate resources away from the treatment of established coronary disease to its prevention at the earliest possible juncture. In the words of the poet William Wordsworth in 1802, “the child is father of the man.”
Dr. Hecht is a consultant to Philips Medical Systems.
↵⁎ 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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