CLINICAL RESEARCH: PEDIATRIC CARDIOLOGY
Cardiac Markers of Pre-Clinical Disease in Adolescents With the Metabolic SyndromeThe Strong Heart Study
Marcello Chinali, MD*, ,*,
Giovanni de Simone, MD*,,
Mary J. Roman, MD,
Lyle G. Best, MD ,
Elisa T. Lee, PhD ,
Marie Russell, MD||,
Barbara V. Howard, PhD|| and
Richard B. Devereux, MD
* Department of Clinical and Experimental Medicine, "Federico II" University Hospital School of Medicine, Naples, Italy
Department of Medicine, Weill Cornell Medical College, New York, New York
Missouri Breaks Industries Research, Inc., Timber Lake, South Dakota
University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
|| MedStar Research Institute, Washington, DC
Manuscript received March 5, 2008;
accepted April 5, 2008.
* Reprint requests and correspondence: Dr. Marcello Chinali, Echocardiography Laboratory, Department of Clinical and Experimental Medicine, "Federico II" University Hospital; Ed. 1, Via Sergio Pansini 5, 80131, Napoli, Italy (Email: mchinali{at}unina.it).
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Abstract
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Objectives: Our aim was to evaluate the impact of metabolic syndrome (MetS) on cardiac phenotype in adolescents.
Background: A high prevalence of MetS has been reported in adolescents.
Methods: Four hundred forty-six nondiabetic American Indian adolescents (age 14 to 20 years, 238 girls) underwent clinical evaluation, laboratory testing, and Doppler echocardiography. Age- and gender-specific partition values were used to define obesity and hypertension. Metabolic syndrome was defined according to Adult Treatment Panel III criteria, modified for adolescents. Left ventricular (LV) hypertrophy and left atrial (LA) dilation were identified using age- and gender-specific partition values.
Results: One hundred eleven participants met criteria for MetS. They had a similar age and gender distribution as non-MetS participants. Analysis of covariance, controlling for relevant confounders, demonstrated that participants with MetS had higher LV, LA, and aortic root diameters, higher LV relative wall thickness, and greater LV mass index. Accordingly, MetS participants showed higher prevalences of LV hypertrophy (43.2% vs. 11.7%) and LA dilation (63.1% vs. 21.9%, both p < 0.001) compared with non-MetS participants. In addition, MetS was associated with a reduction in midwall shortening, lower transmitral mitral early to atrial peak velocity ratio, and mildly prolonged mitral early deceleration time (all p < 0.05). In multiple regression analysis, independently of demographics, obesity, blood pressure, and single metabolic components of MetS, clustered MetS was associated with a 2.6-fold higher likelihood of LV hypertrophy and a 2.3-fold higher likelihood of LA dilation (both p  0.02).
Conclusions: In a population sample of adolescents, MetS is associated with higher prevalences of LV hypertrophy and LA dilation and with reduced LV systolic and diastolic function, independently of individual MetS components.
Key Words: children • hypertension • obesity • left ventricular hypertrophy • left atrium • echocardiography • population study
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Abbreviations and Acronyms
| | BMI = body mass index | | CI = confidence interval | | CV = cardiovascular | | HDL-C = high-density lipoprotein cholesterol | | LA = left atrium/atrial | | LV = left ventricle/ventricular | | MetS = metabolic syndrome | | OR = odds ratio | | RWT = relative wall thickness | | RWTa = relative wall thickness age-adjusted |
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The metabolic syndrome (MetS) is characterized by clusters of metabolic risk factors (1), which might increase cardiovascular (CV) risk beyond what is predicted by single components (2–5). The MetS is associated with an increased risk of cardiac mortality in the absence of diabetes and independently of arterial hypertension (6–8). It has been previously reported that MetS is related to abnormal left ventricular (LV) geometry and function in nondiabetic adults with a high prevalence of obesity, and that increased blood pressure is the MetS component most strongly associated with markers of pre-clinical CV disease even in the absence of traditionally defined hypertension (9).
The rising prevalence of obesity and hypertension among children and adolescents is now a major health concern with both epidemiological and economic implications (9–12). We have already reported that LV hypertrophy can be found in 30% of obese adolescents at a mean age <18 years, despite a low prevalence of hypertension (13). And it has also been observed that obese adolescents often have MetS, suggesting that the increased LV mass might be a response not only to increased hemodynamic load but also to possible neurohormonal effects of clustered metabolic factors influencing LV growth (13). To date, little information is available on whether the presence of MetS is associated with significant cardiac abnormalities in adolescents, or whether the impact of MetS on cardiac phenotype is independent of the single components of the syndrome. Accordingly, the present analysis has been designed to study the CV effects of MetS in adolescents from a population-based sample.
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Methods
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Study population.
The SHS (Strong Heart Study) is a longitudinal study of CV risk factors and prevalent and incident CV disease in American Indian communities in Arizona, Oklahoma, and North/South Dakota. As previously described (14), 4,549 members of 13 tribes age 45 to 74 years were recruited from defined sampling frames (overall participation rate >61%) for baseline examination in July 1989 to January 1992. The fourth SHS examination (13), conducted in 2001 to 2003, enrolled members of large 3-generation families, ascertained by having multiple family members in the initial SHS cohort, which included a total of 460 adolescent participants (age <20 years, mean 17.3 ± 1.5 years; 53.2% female participants). After excluding participants with American Diabetes Association–defined diabetes (n = 10) and/or significant valvular disease (n = 4), 446 adolescents (14 to <20 years of age) were included in the present analysis.
Physical examination and laboratory testing.
The examination included medical history, computerized electrocardiogram, measurement of brachial blood pressure, fasting glucose and insulin, glycated hemoglobin, lipid and lipoprotein levels, and a 2-h, 75-g glucose tolerance test (15). Blood pressure was measured as recommended by the Fifth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (15). Laboratory tests and anthropometric measures (weight, height, and waist circumferences) were taken as previously reported (16). Fat-free mass and adipose body mass were estimated by the use of an RJL impedance meter (model B14101
[GenBank]
, RJL Equipment Co., Clinton Township, Missouri) and equations based on total body water validated in the American Indian population (17).
Definition of obesity, hypertension, and MetS.
As recommended, 95th percentiles of body mass index (BMI)-for-age charts developed by the National Center for Health Statistics (18) were used to define obesity. Guidelines correction was applied (19) so that the limit separating overweight and obesity did not exceed a BMI of 30 kg/m2.
For adolescents 18 years of age and younger, hypertension was assessed by using age-, gender-, and height-specific partition values according to the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents (20). For adolescents older than 18 years of age, recommendations from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure were followed (21). The MetS was preliminarily identified using the Adult Treatment Panel III (ATP III) (22) definition (with partition value of 100 mg/dl for fasting glucose), and then applying the ATP III modified definition developed by Jolliffe and Janssen (23) for adolescents. Under both criteria, MetS was diagnosed when at least 3 of the 5 components of the syndrome (increased waist circumference, high blood pressure, high triglycerides, high fasting glucose, and low high-density lipoprotein cholesterol [HDL-C]) exceeded age- and gender-specific partition values (Online Appendix).
Echocardiography.
Echocardiograms were performed by expert sonographers, according to standardized methods, and reviewed off-line by 2 independent readers (M.C., R.B.D.) using a computerized review station with digitizing tablet and monitor screen overlay for calibration and performance of needed measurements (24). Left ventricular internal dimension, and septal and posterior wall thickness were measured at end-diastole and -systole by American Society of Echocardiography recommendations on 3 cycles (25,26). As previously described (27), left atrial (LA) anteroposterior diameter was measured in long-axis views in end-systole, and aortic root diameter was measured at the level of the sinus of Valsalva in end-diastole. Since normal LA size in children increases with growth (28), LA diameter was normalized for body height to account for differences in body maturation. Partition values to detect LA dilation were 2.23 cm/m in boys and 2.11 cm/m in girls, representing age-, gender-, and ethnic-specific 95th percentiles derived in a subgroup of 92 normal adolescent participants. A necropsy-validated formula was used to calculate LV mass (29), which was normalized for body height in meters to the allometric power of 2.7, which linearizes the relation between LV mass and height (i.e., body growth) and identifies the impact of excess body weight (30). Partition values for the definition of LV hypertrophy were 40.75 g/m2.7 for boys and 38.49 g/m2.7 for girls, representing previously reported age-, gender-, and ethnic-specific cutoff points (13). To evaluate the concentricity of LV geometry, myocardial thickness (wall + septum) was divided by LV minor axis (diameter) to generate relative wall thickness (RWT). Because normal RWT increases with age (31), its raw value was adjusted for age (RWTa) by previously reported equations (31). Left ventricular systolic performance was assessed by LV ejection fraction and by LV shortening measured at the midwall level (midwall shortening) (32). Stroke volume was determined by an invasively validated Doppler method (33) and used to calculate cardiac output.
Left ventricular diastolic properties were assessed by Doppler interrogation of transmitral peak early (E) and late (A) velocities and by measurement of the deceleration time of peak E velocity. Isovolumic relaxation time was measured between mitral valve closure and aortic valve opening.
Statistical analysis.
Statistical analyses were performed using SPSS 12.0.0 (SPSS Inc., Chicago, Illinois) software. Data are presented as mean ± SD for continuous variables and as proportions for categorical variables. Descriptive statistics were based on normal or chi-square distributions. The population was dichotomized according to the presence of MetS. Comparison of demographics and laboratory tests was performed by independent t test. Comparison of cardiac geometry and function was performed by analysis of covariance adjusting for differences in age, gender, heart rate, and body height (considered an estimate of body maturation at a given age and gender). In addition, binary logistic multiple regression modeling was performed, controlling for confounders (age and gender), with the specific aim of determining whether clustered MetS confers additional independent risk of presenting markers of pre-clinical CV disease (i.e., LV hypertrophy and LA dilation) over and above the effects of single-component risk factors. Covariates were entered in the model using a hierarchical enter procedure in the following order: 1) age and gender; 2) presence of obesity; 3) systolic blood pressure; 4) single metabolic components of MetS (including fasting glucose, HDL-C, and triglycerides); and 5) presence of MetS. Alternative models were also performed replacing obesity with waist circumference, and fasting glucose with either plasma insulin or homeostasis model assessment (HOMA) index.
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Results
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Distribution of risk factors.
Adult ATP III criteria for the definition of MetS identified 71 participants with the syndrome (15.9% of population, 53.5% girls). According to the adolescent criteria, MetS was instead present in 111 participants (24.9% of population, 55.9% girls; kappa score between criteria = 0.66) with similar prevalence in women (26.3%) and men (23.3%; p = NS). The most prevalent component of the MetS by the adolescent definition was increased waist circumference (54.3%), followed by low HDL-C (46.4%), high blood pressure (30.3%), increased triglycerides (27.8%), and increased fasting glucose (2.5%). Of the 446 participants, 102 (22.9%) had no component of the MetS, 116 (26%) had only 1 MetS component, 117 (26.2%) had 2 clustered risk factors, 77 (17.3%) had 3, 32 (7.2%) had 4, and only 2 participants (0.4%) showed clustered presence of all 5 risk factors.
Clinical and laboratory characteristics of the population by MetS class.
Participants with MetS had similar age, gender distribution, and heart rate compared with non-MetS participants (Table 1). Comparison of anthropometrics, body composition, and laboratory tests identified the expected unfavorable phenotype in the MetS participants as opposed to non-MetS participants, characterized by higher fat and fat-free body mass, higher BMI, and higher blood pressure values. Prevalences of obesity and hypertension were also significantly higher in MetS participants (both p < 0.001). A similar prevalence of smoking habit and alcohol drinking was observed between the 2 groups (p = NS).
Metabolic characteristics of the study population are shown in Table 2. As expected, participants with the MetS showed a worse glycemic profile (higher fasting glucose, insulin, and HOMA index), worse lipid profile (higher total cholesterol, low-density lipoprotein cholesterol, and triglycerides, and lower HDL-C), and higher values of plasma fibrinogen, with similar plasma creatinine levels between groups.
Cardiac geometric and functional characteristics by MetS class.
After adjustment for age, gender, height, and heart rate, LV chamber size (diameter), aortic root, and LA diameter were greater in MetS adolescents compared with non-MetS adolescents (Table 3). Left ventricular mass and RWTa were also significantly higher in MetS participants (all p < 0.0001). Accordingly, prevalence of LA dilation (63.1% vs. 21.9%) and LV hypertrophy (43.2% vs. 11.7%) were markedly higher in the presence of MetS (both p < 0.001). Stroke volume and cardiac output were increased in MetS participants, due to enlarged LV chamber size. Ejection fraction was similar in the 2 groups; in contrast, midwall shortening was lower in MetS than in non-MetS adolescents. Finally, MetS adolescents exhibited a significantly lower transmitral E/A ratio and slightly longer deceleration time of E velocity, but no significant difference in isovolumic relaxation time. Results were also confirmed when applying adult ATP III criteria for the definition of MetS (data not shown).
Predictors of LA dilation and LV hypertrophy.
In univariate binary logistic regression, LA dilation was predicted mainly by the presence of obesity (odds ratio [OR]: 26.26; 95% confidence interval [CI]: 10.33 to 66.77; p < 0.001) and higher systolic blood pressure (OR: 1.04 per mm Hg; 95% CI: 1.02 to 1.06; p < 0.001), and then by higher triglycerides (OR: 1.01 per mg/dl; 95% CI: 1.00 to 1.02; p < 0.01) and male gender (OR: 1.65; 95% CI: 1.47 to 1.77; p < 0.01), and negatively by higher HDL-C (OR: 0.96 per mg/dl; 95% CI: 0.94 to 0.98; p < 0.01), with no significant impact of fasting glucose or age (p = NS). As shown in Table 4, in hierarchical multivariate regression, male gender (OR: 3.32; 95% CI: 1.80 to 6.13), obesity (OR: 4.17; 95% CI: 2.62 to 6.66; both p < 0.001), and systolic blood pressure (OR: 1.03; 95% CI: 1.01 to 1.06; p < 0.01) still predicted LA dilation, with no significant impact of age and single metabolic components of the MetS. In contrast, a significant effect was observed for clustered MetS, which conferred an additional 2.3-fold increased risk of LA dilation (OR: 2.33; 95% CI: 1.14 to 4.73; p = 0.020), independently of demographics and single components of the syndrome.
Similar results were also observed for LV hypertrophy. In univariate binary logistic analysis, LV hypertrophy was predicted mainly by the presence of obesity (OR: 12.10; 95% CI: 4.29 to 33.99; p < 0.001) and higher systolic blood pressure (OR: 1.03 per mm Hg; 95% CI: 1.01 to 1.06; p < 0.001), and then by higher triglycerides (OR: 1.02 per mg/dl; 95% CI: 1.01 to 1.04; p < 0.05) and older age (OR: 1.19 per year; 95% CI: 1.01 to 1.41; p < 0.05), and negatively by higher HDL-C (OR: 0.96 per mg/dl; 95% CI: 0.94 to 0.99; p < 0.01), with no significant impact of fasting glucose or gender (p = NS). As shown in Table 5, in hierarchical multivariate regression, obesity (OR: 2.38; 95% CI: 1.41 to 4.04) and systolic blood pressure (OR: 1.04; 95% CI: 1.01 to 1.07) still predicted LV hypertrophy (both p < 0.01), with no significant impact of age, gender, or single metabolic components of MetS. In contrast, a significant effect was observed for clustered MetS, which conferred an additional 2.6-fold increased risk of LV hypertrophy (OR: 2.57; 95% CI: 1.21 to 5.44; p = 0.014), independently of demographics and single components of the syndrome. When the smaller number of participants with MetS by the adult ATP III definition was evaluated, no additional independent risk was found for MetS for either LA dilation or LV hypertrophy. Alternative models replacing obesity with waist circumference, and fasting glucose with either HOMA index or insulin did not significantly change the reported results. In particular, no independent impact was observed for plasma insulin (OR: 1.007 per IU/ml; 95% CI: 0.95 to 1.019; p = 0.262) or HOMA index (OR: 1.027; 95% CI: 0.98 to 1.075; p = 0.259).
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Discussion
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The present study provides the first evidence of a strong impact of MetS on cardiac phenotype in an unselected population of adolescents applying criteria for the definition of MetS specifically designed for this age range (23,34–36). To our knowledge, only 1 recent report has attempted to identify a possible independent impact of MetS on CV phenotype in adolescents and has failed to show a significant association between MetS and intima-media thickness (37).
In a previous report that analyzed data of the NHANES (National Health and Nutrition Examination Survey) study, a highly representative study of the U.S., Goodman et al. (34) described a 4.2% prevalence of the MetS in the general adolescent U.S. population, with a markedly higher prevalence, reaching 19.5%, in overweight/obese adolescents when applying adolescent-ATP III criteria. The evidence that MetS is associated with unfavorable CV phenotype and unfavorable clinical outcome even in the absence of overt hypertension and/or diabetes supports the hypothesis that MetS might represent a distinct medical condition, at least from an epidemiological point of view (38). The high prevalence of MetS in adults and adolescents has increased medical attention on the syndrome (11,12,34–36), also considering the increasing burden of obesity and related metabolic complications found in epidemiological surveys in different countries (39).
In the present study, adolescents with MetS exhibit worrisome abnormalities of cardiac geometry and function, including aortic root and LA dilation, a trend towards concentric LV geometry, and a remarkably high prevalence of LV hypertrophy, present in over 40% of MetS adolescents. Furthermore, we found significant impairment in LV wall mechanics and diastolic function (as shown by reduced mitral E/A ratio and prolonged E-wave deceleration time). Interestingly, the negative effect of MetS on cardiac phenotype was independent of the effect of the single risk factors defining the syndrome, consistent with the concept that in adolescents, clustering of risk factors in MetS may predict CV disease above and beyond the risk associated with its single components.
Other authors have reported independent correlations among body size, metabolic abnormalities, and LV mass growth, in children and adolescents (40,41), but MetS has not yet been considered as a pathologic entity in this setting. The Bogalusa Heart study reported an association between insulin and LV mass growth in obese adolescent girls, also independently of blood pressure (42). In the present study, multivariate modeling showed that the MetS is associated with LV hypertrophy and LA dilation independent of the effects of obesity and blood pressure, while single metabolic risk factors are associated with manifestations of pre-clinical CV disease only in univariate regression.
It has been recently reported that the prevalence of MetS varies widely in overweight adolescents depending on the MetS definition used (43) and that the instability in the diagnosis of MetS in adolescents (caused by both gain and loss of the diagnosis) might imply a reduced clinical utility of the syndrome (44). In the present study, we have tested age- and gender-specific criteria for the definition of MetS, proposed with the specific aim of minimizing the instability of the MetS diagnosis in the adolescent age range (23,44). Of note, compared with the adult definition of MetS, the proposed adolescent criteria were able to identify a strong, independent, and additional impact of the MetS on cardiac markers of pre-clinical disease. In addition, although follow-up data for the adolescents included in the present analysis are not yet available, the significant alteration of CV phenotype identified in the presence of MetS strongly suggests that the diagnosis of MetS even obtained from a single clinical examination should encourage prompt lifestyle risk-reducing interventions in otherwise healthy adolescents.
Study limitations.
The present study has been performed on American Indians, an ethnic group in which adolescent-ATP III criteria were not specifically tested in NHANES. However, in our sample of adolescents with a high prevalence of obesity, the MetS was present in 25% of the population, similar to the prevalences reported in NHANES in the obese/overweight U.S. adolescent population (34). As suggested by current guidelines for the definition of MetS, we have applied waist circumference partition values to identify the presence of abdominal obesity, although increasing evidence suggests that a direct measure of intra-abdominal fat should be preferred. However, it has been recently shown in a population-based sample of boys and girls that waist circumference offers a feasible alternative to the magnetic resonance imaging estimation of intra-abdominal adipose tissue (45). Finally, Tanner stage was not determined, and the relation between body maturation and cardiac geometry/function could not be investigated. Of note, both LV mass and LA diameter were indexed by height, a method that has been previously shown to correct for body growth (29); in addition, all but 2 participants were  15 years of age, thereby minimizing the proportion of pre-pubertal participants.
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Conclusions
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In a population-based sample of adolescents, MetS was associated with high prevalences of LV hypertrophy and LA dilation, and with increased aortic root diameter and impairment in both systolic and diastolic LV performance. The impact of the MetS on cardiac markers of pre-clinical disease was independent and additional to obesity, blood pressure, and single metabolic abnormalities, suggesting that, also in adolescents, the risk associated with MetS might be beyond what is predicted by single risk factors. Our findings, paired with previous studies reporting a steep increase in the prevalence of obesity and associated metabolic abnormalities in children and young adults, suggest that the presence of MetS in adolescents should prompt aggressive lifestyle modifications to reduce the increasing burden of future CV disease.
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Appendix
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For a complete explanation of the partition values for the definition of metabolic syndrome, please see the online version of this article.
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Footnotes
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This work was supported by grants HL41642, HL41652, HL41654, HL65521, and M10RR0047-34 (General Clinical Research Centers) from the National Institutes of Health, Bethesda, Maryland.
The views expressed in this study are those of the authors and do not necessarily reflect those of the Indian Health Service.
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Metabolic Syndrome and Cardiovascular Abnormalities in Children
- Stephen R. Daniels
J. Am. Coll. Cardiol. 2008 52: 939-940.
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S. R. Daniels
Metabolic Syndrome and Cardiovascular Abnormalities in Children
J. Am. Coll. Cardiol.,
September 9, 2008;
52(11):
939 - 940.
[Full Text]
[PDF]
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