Background
Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in the adult population. There is increasing evidence to suggest that atherosclerosis begins in childhood, progresses silently for many years and only becomes apparent once clinical manifestations, including myocardial infarction and/or cerebrovascular accident, occur [
1,
2]. Children with rheumatologic disorders may be at increased risk of developing premature atherosclerosis due to both disease specific risk factors, such as chronic inflammation, corticosteroid burden, elevated homocysteine levels and underlying vasculopathy; as well as a host of traditional risk factors, including dyslipidemia, insulin resistance, obesity and hypertension [
3‐
7]. Premature atherosclerosis has been demonstrated among young patients with systemic lupus erythematosus (SLE) and Kawasaki disease (KD), using non-invasive ultrasound techniques including carotid intima-media thickness (CIMT) and flow-mediated dilation (FMD) [
4,
8]. This finding is not surprising given the evidence that atherosclerosis is, in large part, an inflammatory disorder initiated and propagated by both humoral and cellular immunity [
9,
10].
Cardiovascular manifestations of juvenile dermatomyositis (JDM), the most common idiopathic inflammatory myopathy of childhood, include acquired structural abnormalities, ventricular dysfunction, arrhythmias, myocarditis, and hypertension [
11‐
17], with myocardial infarction acting as a rare cause of death [
11,
13,
18,
19]. JDM shares the same atherogenic risk factors and vasculopathic features as those of other rheumatologic illnesses, with the added component of lipodystrophy and its related metabolic derangements [
15,
20,
21]. Moreover, higher rates of traditional atherosclerotic risk factors have been reported in adult patients with idiopathic inflammatory myopathies as compared to the general population [
12,
17,
22].
A potential consequence of the systemic vasculopathy in JDM is endothelial dysfunction, a broad term denoting impaired vasodilation secondary to diminished production or availability of nitric oxide (NO) [
9]. Recognized as an early physiologic precursor of atherosclerosis, endothelial dysfunction can long precede vessel structure changes, which allows it to serve as an independent predictor of future CVD [
9,
23]. Prior investigations of endothelial dysfunction in children have used non-invasive ultrasound techniques, such as brachial artery FMD and pulse wave velocity (PWV) as validated surrogate outcome markers of early atherosclerosis [
20,
24]. These methods correlate with cardiovascular events and severity of coronary artery disease in adults, as confirmed by angiography [
25‐
29]. Further substantiating these tools in children is the association between reduced FMD and the presence of atherogenic risk factors in pediatric patients with KD, familial hypercholesterolemia, type I diabetes mellitus (T1DM), and obesity [
8,
30‐
36]. Despite significant advances in ultrasonographic technology, limitations surround its use, particularly in children [
37]. Endothelial Pulse Amplitude Testing (Endo-PAT) is an FDA approved method of detecting endothelial dysfunction, that is inexpensive, non-invasive, reproducible, and operator independent. It assesses post-occlusive vasodilatory response in the digital arteries and serves as an accurate measure of endothelial function in both central and peripheral circulation in adults [
38,
39].
There is a paucity of data regarding cardiovascular outcomes in children with JDM, and to date, premature atherosclerosis has not been evaluated in these patients. Identification of the earliest stages of the atherosclerotic process in patients with chronic inflammation is critical to the prevention of the long-term morbidity and mortality associated with CVD. The primary aim of this study was to determine the underlying frequency of premature atherosclerosis and atherogenic risk factors in children with JDM, as compared to pediatric controls, using flow-mediated dilation as a measure of endothelial function. The secondary aim was to evaluate the potential association of endothelial dysfunction with these atherogenic risk factors.
Discussion
Children with JDM, similar to other rheumatic diseases, may be at increased risk of premature atherosclerosis due to a host of traditional and non-traditional atherogenic risk factors. Typical contributing factors to poor outcomes in JDM include younger age at presentation, high initial serum CPK, longer disease duration, and complications including calcinosis and lipodystrophy [
47]. It is unknown, however, to what extent these contribute to cardiovascular prognosis. To our knowledge, this is the first study to evaluate the frequency of premature atherosclerosis, as measured by endothelial dysfunction, in a racially diverse pediatric population with JDM.
Although there are no prior studies examining the prevalence of premature atherosclerosis in children with JDM, two small case-control studies have been performed assessing the cardiovascular outcomes of patients with history of JDM in childhood. The first involved 59 patients with JDM (mean age 16.8, range 2–38 years), in which a higher prevalence of hypertension and ventricular diastolic dysfunction was seen as compared to healthy age- and gender- matched controls [
16]. In this study, a significant association was found between cardiac dysfunction and early disease activity (one-year post diagnosis). A second pilot study found increased cardiovascular risk factors and evidence suggestive of premature atherosclerosis in 8
adults with a prior history of JDM (median age: 38 years old), as compared to healthy controls. In this study, the adult patients with a history of JDM exhibited increased atherogenic risk factors (including higher blood pressure, lower adiponectin, less upper arm fat and increased proinflammatory oxidized HDL), as well as significantly increased CIMT and decreased FMD, as compared to healthy controls [
48].
In our study, we found a statistically significant difference in endothelial function between JDM patients and pediatric controls when controlled for hsCRP or lipoprotein A, whereas our population of pediatric controls appeared to demonstrate a reduced post-occlusive hyperemic response (i.e. reduced RHI), and thus worse endothelial function, as compared to JDM patients. Although of borderline statistical significance, pediatric controls appeared to have higher levels of lipoprotein A, one of traditional atherogenic risk factors, which was an important confounder in our results. Lipoprotein A, independent of other lipids, has been associated with abnormal FMD and is an independent risk factor for premature atherosclerosis by causing impaired endothelium-dependent vasodilation of angiographically normal coronary arteries [
31,
49,
50]. Similarly, hsCRP which was slightly higher in control patients was a confounder in the association between JDM status and endothelial dysfunction. This raises that question of whether the true inflammatory burden in JDM may be less than that of other rheumatic diseases (such as SLE) or whether achieving adequate disease control (as was seen in our patient sample), impacts overall endothelial function.
Interestingly, BMI was positively associated with RHI only in the JDM cohort, implying better endothelial function in the overweight/obese patients. This finding could possibly be explained by the potential beneficial effects that corticosteroids may have had on the vascular endothelium in JDM patients, while simultaneously contributing to their increasing BMI. A recent study highlights the conflicting impact that corticosteroids may have on endothelial function in patients with inflammatory diseases; whereas direct deleterious effects on the endothelium may be seen, these may be outweighed by the positive impact of reducing vascular inflammation [
51]. We speculate that in the JDM patients, BMI was likely elevated due to a known side effect of steroid toxicity. Therefore, JDM patients with increasing BMI may have been simultaneously benefiting from reduced vascular inflammation and potentially reduced endothelial dysfunction. This theory may be supported by the fact that the majority of our JDM patients demonstrated minimal evidence of disease activity at the time of the study. In contrast, in control subjects, BMI was not found to be protective and may represent a group of patients with dietary/familial induced obesity and thus potentially increased traditional atherosclerotic risk factors.
An additional consideration in the interpretation of our results is the impact that race, income and social disparities have on chronic disease and future comorbidities. The participants in this study primarily represent a population of Black and Hispanic youth from low income households in an inner-city clinic. Previous studies have demonstrated that racial and ethnic disparities are associated with worse morbidity and adult outcomes in children with chronic disease, including JDM [
52‐
54]. Although it is difficult to apply adult cutoffs to children, in this study, 63% of our total group demonstrated endothelial dysfunction based on the adult RHI cutoff of 1.67. Similarly, the median RHI = 1.57 in our overall study population is lower than previously described in healthy adolescents (1.78) and children with TIDM (1.63) [
32,
46]. In our study, over half of pediatric controls were from a minority racial/ethnic background and a majority from a household with a medium income of less than $50,000 per year. Due to the rarity of disease, families of children with JDM often travel from further distances to seek a specialized academic center and therefore were more likely to represent a racially and financially diverse population in our sample. Put together, these findings raise concern for the risk of endothelial dysfunction in young children, particularly across varying racial and socioeconomic groups. To what extent each of the proposed risk factors (traditional versus sociodemographic versus disease specific) play in the ultimate development of CVD is yet to be determined.
There are several limitations of this work that need to be overcome in further studies. First, the sample size was restricted due to the rarity of JDM, and thus multiple confounding risk factors could not be adjusted for together in a single multivariable analysis, which lacks generalizability of these results. It is also noted that although Endo-PAT is designed to detect the earliest signs of endothelial dysfunction, its prior use in very young children is limited. The feasibility of this test is dependent on cooperation of the child with minimal movement of the extremities during the course of the examination; any movements may have created artifact that could have altered the findings of this study. The Endo-PAT RHI calculation is specifically designed to correct for any detected artifact to assure the validity of the results. To address this concern more diligently, all study reports were examined by the manufacturer for quality assurance.
Conclusions
With progress in the treatment of rheumatologic diseases rapidly advancing, life expectancy has greatly improved, making complications of premature atherosclerosis a potential cause of morbidity and mortality in these patients. In this study, we have shown that atherogenic risk factors are present in the pediatric population and may be associated with endothelial dysfunction, even at very young ages. However, despite increasing concerns that children with rheumatologic disorders may be at increased risk of developing premature atherosclerosis, traditional and sociodemographic features may play a greater role in the ultimate development of cardiovascular disease. Increased awareness of premature atherosclerotic disease in all young children will allow for increased surveillance of modifiable atherogenic risk factors (both traditional and non-traditional) and the optimization of long-term clinical care.
Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit
http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (
http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.