Pediatric Cardiology

, Volume 32, Issue 5, pp 628–633

Cross-Sectional Analysis of Cardiovascular Risk Factors in Children With Parental History of Premature Ischemic Heart Disease

Authors

  • Gal Neuman
    • Department of PediatricsMeyer Children’s Hospital
    • Technion Faculty of Medicine
    • Department of PediatricsMeyer Children’s Hospital
    • Technion Faculty of Medicine
  • Doron Aronson
    • Technion Faculty of Medicine
    • Department of CardiologyRambam Health Care Campus
  • Avraham Lorber
    • Technion Faculty of Medicine
    • Department of Pediatric CardiologyMeyer Children’s Hospital
  • Diana Gaitini
    • Technion Faculty of Medicine
    • Department of Medical ImagingRambam Health Care Campus
  • Roy Onn
    • Department of PediatricsMeyer Children’s Hospital
    • Technion Faculty of Medicine
  • Naim Shehadeh
    • Department of PediatricsMeyer Children’s Hospital
    • Technion Faculty of Medicine
Original Article

DOI: 10.1007/s00246-011-9931-x

Cite this article as:
Neuman, G., Shavit, I., Aronson, D. et al. Pediatr Cardiol (2011) 32: 628. doi:10.1007/s00246-011-9931-x
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Abstract

This study aimed to evaluate the presence of cardiovascular risk factors in children with a parental history of premature ischemic heart disease (two- or three-vessel disease diagnosed before the age of 55 in men and 65 in women). A prospective cross-sectional study was performed on 55 children. The following parameters were assessed: body mass index (BMI), waist and hip circumference, blood pressure, lipids profile, fasting glucose (FG), C-reactive protein (CRP), and carotid intimal-medial thickness (CIMT). Twenty-eight children had hypercholesterolemia, and 11 had other forms of dyslipidemia. Sixteen children had a high BMI; 17 had increased CRP levels; 2 were hypertensive; and 2 had impaired FG. CIMT levels were not correlated with age (Pearson r = −0.486; p = 0.78) and height (Pearson r = −6.31; p = 0.84), but they were correlated with cholesterol levels (Spearman r = 0.375; p < 0.005). Most patients (83%) had ≥2 risk factors; half of them had ≥3 risk factors. We concluded that these at-risk children should be carefully screened for all known risk factors.

Keywords

Ischemic heart diseaseCardiovascular diseaseRisk factorsChildrenParental

Background

Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in the developed world. Most of the clinical burden of CVD occurs in adulthood [2, 8]. However, research during the last 40 years has increasingly indicated that the process of atherosclerotic CVD begins early in life and is progressive throughout the life span [15]. It has also become clear that there is an important genetic component to the disease process, which produces susceptibility, and that environmental factors, such as diet and physical activity, are equally important in determining the course of the disease process [5].

Screening is a universally accepted method for the primary prevention of CVD in adults. However, screening for cardiovascular risk factors in children and adolescents is a challenging issue because there is no strict consensus in regard to screening those <18 years of age [13]. Unlike adults, for whom the Framingham risk score is used, screening among younger individuals is based on a few known risk factors for ischemic heart disease (IHD), such as obesity, metabolic syndrome, and serum lipid profile [8].

Current American recommendations advocate selective screening of children with parental history of premature IHD (PHPIHD) or high blood concentrations of cholesterol. This approach also advocates screening pediatric patients for whom family history is not known or those with other risk factors for CVD, such as obesity, hypertension, and diabetes mellitus [8]. However, studies evaluating the efficacy of the guidelines for such a targeted approach show that fewer than half of children and adolescents have had their cholesterol levels measured on the basis of a positive family history of CVD or increased cholesterol concentration [9].

There is a paucity of reports in the literature on cardiovascular risk factors other than hypercholesterolemia in children with PHPIHD. The few available studies have demonstrated that dyslipidemia, and in particular hyperlipidemia, were associated with high risk for developing CVD [16, 17].

The primary objective of the present study was to determine the frequency of risk factors for developing CVD and their aggregation.

Patients and Methods

Subjects and Study Design

A prospective cross-sectional study was designed. In 2008, a new service designated for the assessment and follow-up of children with high risk for CVD was established in the Pediatric Cardiology Clinic of the Rambam Health Care Campus (RHCC) in northern Israel. Children who were referred to this clinic had PHPIHD, defined (by the adult cardiologists of the RHCC) as two- or three-vessel disease diagnosed before the age of 55 in men and 65 in women. During the 1-year study period (from January 1, 2008, to December 31, 2008), we tested any new referral to this clinic for the presence of known risk factors for CVD. The study was approved by the RHCC Helsinki Committee.

Study Measurements

All of the subjects underwent the following evaluations.

Anthropometric Measurements

Anthropometric measurements included height, weight, BMI, waist and hip circumferences, and waist-to-height ratio, which was calculated by dividing the subject’s waist circumference by his or her height. The waist was measured at the narrowest point, between the bottom rib and the top of the hip bone, usually 1 cm above the umbilicus. A waist-to-height ratio <0.5 is generally considered normal [7].

Noninvasive Blood Pressure Measurements

For noninvasive blood pressure measurements, we used the auscultatory method with a stethoscope and a mercury sphygmomanometer. Blood pressure was measured after 5 min of rest in a quiet environment. The child was seated with his or her back with feet in a supported position. An appropriate cuff size was used for the patient’s arm circumference.

Blood Analyses

Blood analyses included fasting serum lipid profile (total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], triglycerides) and high-sensitivity serum C-reactive protein (CRP). Febrile illness was ruled out for the 2 weeks before blood analysis. The blood tests were taken after the subjects had been fasted for 14 h. Total cholesterol, HDL, and triglyceride levels were measured using enzymatic procedures and spectrophotometric detection techniques (Dimension RxL, Siemens, Munich, Germany). LDL levels were calculated using the following formula (Eq. 1):
$$ {\text{LDL}} = {\text{CHOL-}}1/5{\text{TG-HDL}} $$
(1)

High-sensitivity C-reactive protein (hs-CRP) was measured with latex-enhanced immunonephelometry on a BN-ProSpec nephelometer, Siemens (Munich, Germany). The assay has a detection limit of 0.175 mg/l. The intra-assay coefficient of variation for CRP in our laboratory was 3.3%, and the interassay coefficient of variation was 3.2%.

Measurement of Carotid Intimal-Medial Thickness

Measurement of carotid intimal-medial thickness (CIMT) with B-mode ultrasound of the carotid artery is a noninvasive, sensitive, and reproducible technique for identifying and quantifying subclinical vascular disease and for evaluating CVD risk in adults [22]. CIMT measurements were performed in accordance with the recommendations of the American Society of Echocardiography’s Carotid Intimal-Medial Thickness Task Force [22]. Measurements were performed on the distal 1 cm of the common carotid artery on each side. Electronic calipers were manually located on the two echogenic lines. Three measurements were taken from each sagittal scan, and the obtained values were averaged. Mean CIMT values for each side were reported, and when plaques were present, their location and size were noted. The measurements were performed by trained technicians, and the results were reviewed and randomly remeasured by an ultrasonographist specifically trained in CIMT measurement, thus minimizing interobserver variability. The equipment used for measuring CIMT consisted of Philips HD 5000 and Philips IU 22 equipment (Philips Medical Systems, Bothell, WA, USA), with a high-resolution 5- to 17-MHz linear array transducer. Digital imaging acquisition and storage were in DICOM (digital imaging and communication in medicine) format in a PACS (picture archiving and communication system) system.

Study Definitions

Definitions used in this study were adopted from previous studies as follows.

Hypercholesterolemia

Hypercholesterolemia was defined as increased levels of total cholesterol or LDL cholesterol. We considered increased LDL levels as ≥130 mg/dl (3.37 mmol/l) based on National Cholesterol Education Program guidelines [1].

Dyslipidemia

Dyslipidemia was defined as low HDL level and/or hypertriglyceridemia. We compared these values with age- and sex-matched percentiles (<5th percentile for HDL cholesterol and >95th percentile for triglycerides) based on data from the Lipid Research Clinic Program Prevalence Study [23].

Obesity

Obesity was defined on the basis of age- and sex-matched BMI percentiles [7]. The 85th to the 95th percentile is considered at risk for being overweight, and overweight is defined at ≥95th percentile [7].

Hypertension

Hypertension was defined as the mean of ≥3 systolic or diastolic pressures ≥95th age-, sex-, and height-matched percentiles [14].

Impaired Fasting Glucose

Impaired fasting glucose was defined as a serum glucose level >140 mg/dl (7.8 mmol/l) but <200 mg/dl (11.1 mmol/l) at 2 h after glucose ingestion. Diabetes mellitus was defined as a fasting glucose level >126 mg/dl (7 mmol/l) [24].

Increased CRP Levels

Increased CRP levels were defined as hs-CRP levels ≥1.5 mg/dl (14.3 nmol/l) [18].

Statistical Analysis

Univariate analyses between CIMT and age and between CIMT and height were performed using Pearson’s correlation coefficient parametric test. Spearman’s rank correlation coefficient nonparametric test was used to calculate the correlation between CIMT and total cholesterol. Unpaired Student t test was used to compare data from Arab and non-Ashkenazi Jewish children. The male-to-female ratio was compared using the Fisher’s exact test. All statistics were calculated using StatsDirect statistical software (v2.6.6; StatsDirect Limited, Cheshire, UK).

Results

Demographic Characteristics

Fifty-five children, including 29 boys and 26 girls, with a positive PHPIHD were enrolled in the study. In 53 children, the parental IHD was of paternal origin. Subjects’ ages ranged from 5 to 18 years [mean of 11.6]. Distribution by ethnic origin was 9 Ashkenazi Jewish, 21 non-Ashkenazi Jewish, and 25 Arab children.

Anthropometric Measures

Sixteen children (30%) had a BMI of ≥85th percentile. Of these 16 children, 8 (50%) had a BMI > 95%, which is defined as overweight. The other 8 children (50%) who had a BMI < 95% were at risk for being overweight. Waist-to-height ratio was ≥0.5 in 32% of the children. Mean BMI was significantly greater in the non-Ashkenazi Jewish children than in the Arab children (Table 1).
Table 1

Comparison between Arab and Jewish children with parental history of premature IHD for the presence of cardiovascular risk factors

Cardiovascular risk factors

Non-Ashkenazi Jews (n = 21)

Arabs (n = 25)

p

M/F ratio

8/21

15/25

0.236

Mean age (years)

12.61

10.65

0.128

Mean weight (kg)

50.8

41.5

0.123

Mean height (cm)

1.48

1.42

0.364

Mean BMI (%)

21.97

19.23

<0.05

Mean total cholesterol (mg/dl)

176.95

235.4

<0.0001

Mean LDL (mg/dl)

111.95

174.92

<0.0001

Mean HDL (mg/dl)

48.90

47.52

0.538

Mean triglycerides (mg/dl)

80.47

77.20

0.735

Mean CIMT (cm)

0.053

0.055

0.563

CRP (mg/l)

1.73

1.19

0.259

Lipid Profiles

Dyslipidemia was found in 37 children (67%), 28 of whom (51%) had hypercholesterolemia. Of these 28 children, 26 had LDL levels ≥160 mg/dl (4.14 mmol/l), and 2 had LDL levels between 130 (3.37 mmol/l) and 160 mg/dl. Five children had increased triglycerides but normal LDL and HDL levels. Three children had both increased LDL and hypertriglyceridemia, one with normal HDL. One child had both hypertriglyceridemia and low HDL levels. Greater levels of LDL and total cholesterol were found in Arab children compare with non-Ashkenazi Jewish children (p < 0.0001 and p < 0.0001, respectively) (Table 1).

Blood Pressure, Fasting Glucose Levels, and CRP

Two children were hypertensive, and two had impaired fasting glucose levels. All four children were at risk for being overweight. Seventeen children (31%) had an hs-CRP level ≥1.5 mg/l (14.3 nmol/l).

CIMT Values

CIMT levels were not correlated with age (Pearson r = −0.486; p = 0.78) and height (Pearson r = −6.31; p = 0.84), but they were correlated with cholesterol levels (Spearman r = 0.375; p < 0.005) (Fig. 1). Two subjects had plaques detected on ultrasound. Their LDL levels were 250 and 190 mg/dl (4.92 mmol/l), respectively. Both of their families were diagnosed with familial hypercholesterolemia.
https://static-content.springer.com/image/art%3A10.1007%2Fs00246-011-9931-x/MediaObjects/246_2011_9931_Fig1_HTML.gif
Fig. 1

Relationship between serum total cholesterol and CIMT values. CIMT measured in centimeters; T-CHOL total cholesterol (in mg/dl)

Distribution of Risk Factors

Five children (9%) had clusters of 5 risk factors, and 8 children (15%) had clusters of 4 risk factors. Forty-six children (83%) suffered from ≥2 risk factors, and 26 children (51%) had >2 risk factors.

Discussion

Our study is the first to analyze several cardiovascular risk factors in children with PHPIHD. Two major findings emerged from this analysis:
  1. 1.

    Hypercholesterolemia was detected in half of the children and dyslipidemia in two thirds of them.

     
  2. 2.

    Most patients (83%) had combinations of ≥2 risk factors, and half of them had ≥3 risk factors.

     

IHD is among the most common causes of morbidity and mortality worldwide, and the prevention of IHD is a major challenge for health communities worldwide. The Bogalusa heart study was the first to reveal that a positive parental history of IHD is an independent risk factor for developing obesity, diabetes, dyslipidemia, and other cardiovascular risk factors [10]. Screening is a universally accepted method for the primary prevention of cardiovascular disease in adults. However, there is not as much consensus on screening in children, which is a more complicated issue [13].

Our study supports the recommendations of the American Academy of Pediatrics (AAP) for early screening of serum lipid profile and underlines the importance of early screening for hypercholesterolemia in children of parents with premature IHD. It is worth noting that patients selection for this study was based on a restrictive measure of parental coronary artery disease risk, i.e., two- to three-vessel disease, whereas the criteria for screening by the AAP is a family history of premature CVD, parental history of hypercholesterolemia, or other parental CVD risk factors.

The incidence of hypercholesterolemia found in our sample (51%) is similar to that found in a previous study investigating children with PHPIHD (54%) [17]. However, another study recorded an incidence of 29% for high and borderline/high levels of LDL cholesterol [16].

Other cardiovascular risk factors were also detected in our study. Fifteen percent of our subjects were found to be overweight. This rate is significantly greater than the 3–4% prevalence of overweight subjects previously reported in Israeli population-based studies [3, 12]. The analysis also showed that compared with non-Ashkenazi Jewish children, Arab children had greater levels of LDL and cholesterol but lower BMI levels. Our literature search did not reveal any study that compared at-risk Arab with Jewish children. The greater rate of hypercholesterolemia found in the Arab group may reflect the influence of genetic factors in this population, as previously reported [20].

Two of the eight obese children (25%) in our study had hypertension, resembling the prevalence of hypertension among obese children found in the Israeli population study [3]. Another two of the eight obese children (25%) had impaired fasting glucose levels, which matches the 25% incidence of impaired fasting glucose levels reported by Shina et al. [21].

CRP has been well established as an important marker of cardiovascular risk in adults [18]. A previous study demonstrated that CRP is an important marker of IHD among the Israeli adult population [25]. The relatively high incidence of subjects (31%) with increased CRP in our study further suggests that CRP is an important risk factor.

An important finding of our study is the correlation found between the CIMT and cholesterol levels. Previous studies have demonstrated that the presence of risk factors for CVD in adolescents is significantly correlated with increased CIMT in adulthood [6, 19]. Our findings are consistent with a previous study investigating CIMT in the pediatric population, which demonstrated a positive correlation between CIMT levels and cholesterol levels, age, and height, and a cutoff CIMT level of 0.042 cm in accordance with the 75th percentile [11]. In our study, 86% of the hypercholesterolemic children had CIMT levels ≥0.042. Another study showed increased CIMT levels in children with parental history of premature myocardial infarction [4].

Our results showed that many of the children with PHPIHD had combinations of cardiovascular risk factors. Eight children (15%) had clusters of four risk factors, and five (9%) even had clusters of five risk factors. Although our literature search did not reveal any study that investigated combinations of cardiovascular risk factors among children with PHPIHD, we strongly believe that a search for such a combination of risk factors is extremely important to facilitate appropriate preventative therapy in children with PHPIHD. We speculate that children who have four or five risk factors are at a greater risk for developing early IHD compared with children with one or two risk factors. However, further research is needed to confirm this hypothesis.

Limitations of the Study

Our study has several limitations. The study sample was relatively small, and no control group was enrolled. Moreover, we studied a selective group of Israeli children. The ethnic structure of the study population may have a different prevalence of CVD than that of American or European adults. Therefore the conclusions of this study may not apply to other countries.

Conclusion

This pilot study demonstrated that a relatively high proportion of children with parental history of premature IHD have combinations of risk factors. We recommend that these children be carefully screened for all known cardiovascular risk factors.

Acknowledgment

We thank Michal Rosenberg, Pediatric Clinical Dietician, for her ongoing help on this project.

Conflict of interest

The authors declare that they have no conflict of interest.

Copyright information

© Springer Science+Business Media, LLC 2011