Body Comp Case Study

Relationship of Cardiac Structure and Function to Cardiorespiratory Fitness and Lean Body Mass in Adolescents and Young Adults

with Type 2 Diabetes Fida Bacha, MD1, Samuel S. Gidding, MD2, Laura Pyle, PhD3, Lorraine Levitt Katz, MD4, Andrea Kriska, PhD5,

Kristen J. Nadeau, MD, MS6, Joao A.C. Lima, MD7, on behalf of the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study Group*

Objective To investigate the relationships of cardiac structure and function with body composition and cardiore- spiratory fitness (CRF) among adolescents with type 2 diabetes in the Treatment Options for Type 2 Diabetes in Adolescents and Youth study. Study design Cross-sectional evaluation of 233 participants (median age 18.3 [min-max 12.4-24.2] years, 63% females, median hemoglobin A1c 6.8%) who had echocardiography measurements of left ventricular (LV) mass, ejection fraction, left atrial dimensions, LV diastolic function (early transmitral flow velocity to early mitral annular velocity ratio from tissue Doppler imaging), and right ventricular function (tricuspid annular plane systolic excur- sion [TAPSE]) and body composition (dual-energy x-ray absorptiometry) and CRF (cycle ergometry determination of physical work capacity at heart rate of 170 beats per minute). Results LV mass correlated positively with CRF (r = 0.5, P < .0001), lean body mass (LBM) (r = 0.7, P < .0001), and fat mass (FM) (r = 0.2, P = .00047); LV ejection fraction did not. Early transmitral flow velocity to early mitral annular velocity was positively related to FM (r = 0.14, P = .03) and % body fat (r = 0.18, P = .007), and left atrial internal di- ameter correlated with FM (r = 0.4, P < .0001), LBM (r = 0.3, P < .001), and CRF (r = 0.2, P = .0033). TAPSE weakly correlated with CRF (r = 0.2, P = .0014) and LBM (r = 0.13, P < .05) but not with FM. In multivariable regression analy- ses, LBM (b = 2.13, P < .0001) and CRF (b = 0.023, P = .008) were related to LV mass independent of race, sex, age, hemoglobin A1c, hypertension, smoking, and diabetes medications. CRF (b = 0.0002, P = .0187) and hemoglobin A1c (b = −0.022, P = .0142) were associated with TAPSE. Conclusions In youth with type 2 diabetes, LV size is related to physical fitness. LV ejection fraction is within normal limits. LV diastolic function is inversely related to FM. Greater fitness may counteract adverse effects of poor glycemic control on right ventricular function. (J Pediatr 2016;177:159-66). Trial registration ClinicalTrials.gov: NCT00081328

The findings from the Treatment Options for Type 2 Diabetes in Adoles-cents and Youth (TODAY)1 indicated a high rate of dyslipidemia,microalbuminuria, and hypertension in youth with type 2 diabetes (T2D) at baseline, with progression of these cardiovascular risk factors over time.2,3 Almost one-third of participants met criteria for the diagnosis of hypertension during an average period of 3.9 years of follow-up. Echocardiography performed in the last year of the study at a median of 4.5 years from diagnosis of T2D, and at an average age of 18 years, demonstrated high left ventricular (LV) mass associated with greater body mass index (BMI), greater blood pressure (BP), male sex, and African

BMI Body mass index BP Blood pressure CRF Cardiorespiratory fitness DXA Dual-energy x-ray absorptiometry FM Fat mass E/Em Early transmitral flow velocity

to early mitral annular velocity HbA1c Hemoglobin A1c HR Heart rate LA Left atrium/atrial LBM Lean body mass LV Left ventricle/ventricular M Metformin alone

M + L Metformin plus an intensive lifestyle program

M + R Metformin plus rosiglitazone PWC-

170 Physical work capacity at a heart rate

of 170 beats per minute RV Right ventricle/ventricular TAPSE Tricuspid annular plane systolic

excursion TODAY Treatment Options for type 2 Diabetes

in Adolescents and Youth 2D 2-dimensional T2D Type 2 diabetes

From the 1Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX; 2Nemours Cardiac Center, A.I. DuPont Hospital for Children, Wilmington, DE; 3Department of Pediatrics, School of Medicine, University of Colorado Denver, Aurora, CO; 4Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 5Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA; 6Children’s Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO; and 7Departments of Medicine, Radiology and Epidemiology, Johns Hopkins University, Baltimore, MD *List of members of the TODAY Study Group are available at www.jpeds.com (Appendix 1).

Funding information is available at www.jpeds.com (Appendix 2). Donations received from the following, but none participated in study design, conduct, data analysis, or report: Becton, Dickinson and Company, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, LifeScan, Inc, Pfizer, and Sanofi Aventis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the views of the respective Tribal and Indian Health Service Institution Review Boards or their members. L.K. is a consultant for Takeda and Janssen pharmaceutical. S.G. served as an Editorial Board member of The Journal of Pediatrics (2010-2015). The other authors declare no conflicts of interest.

Portions of the study were presented as an oral abstract at the meeting of the American Diabetes Association, San Francisco, CA, June 13-17, 2014.

0022-3476/$ - see front matter. © 2016 Elsevier Inc. All rights

reserved.

http://dx.doi.org10.1016/j.jpeds.2016.06.048

THE JOURNAL OF PEDIATRICS • www.jpeds.com ORIGINAL ARTICLES

159

American race/ethnicity.4 Physical activity measurements and physical fitness testing highlighted the sedentary nature and low overall fitness levels of this group of adolescents in com- parison with data on obese youth from the National Health and Nutrition Examination Survey and other clinical studies.5

We sought to better understand echocardiographic determi- nants of cardiac structure and function and their relationship to fitness in T2D youth from TODAY. In healthy children, lean body mass (LBM) is a stronger determinant of LV mass than fat mass (FM).6 In a group of lean and overweight 13-year-old children, a positive correlation was found between LV mass index and both lean mass and FM.7 Exercise training at high intensity increases LV mass, but data on the relationship between fitness and heart size in obese youth with T2D are lacking.

We hypothesized that body composition and cardiorespi- ratory fitness (CRF) are associated with cardiac structure and function in obese adolescents with T2D. Therefore, we evalu- ated the relationships of measures of LV structure, LV sys- tolic and diastolic function, as well as right ventricular (RV) function, with body composition and CRF in TODAY par- ticipants, while adjusting for diabetes treatment, glycemic control, and cardiovascular disease risk factors, including race, sex, BP, and smoking.

Methods

The TODAY study population consisted of 699 youth ≥85th percentile for BMI, aged 10-17 years, diagnosed with T2D ≤2 years, and negative for pancreatic autoantibodies (ClinicalTrials.gov: NCT00081328). Participants were ran- domized to 1 of 3 treatment arms: metformin alone (M), metformin plus rosiglitazone (M + R), and metformin plus an intensive lifestyle program (M + L). The primary outcome was defined as failure to maintain glycemic control (hemoglobin A1c [HbA1c] < 8%) on randomized treatment. At this point, insulin therapy was initiated and rosiglitazone was discontin- ued. Treatment with M + R was superior to M in preventing the need for chronic insulin therapy; M + L was not different from M or M + R.1 The protocol was approved by the Insti- tutional Review Boards for the Protection of Human Sub- jects of each participating institution. All participants provided informed consent/assent according to local guidelines.

Cardiovascular Risk Assessment and Treatment BMI was calculated from height and weight (weight in kilo- grams divided by height in m2). BP was taken with a CAS 740 monitor (CAS Medical Systems Inc, Branford, Connecticut) with standardized oscillometric cuff sizes. Participants with hy- pertension (defined as BP ≥95th percentile for age, sex, and height or ≥ 130/80 mm Hg, whichever was lower) received dietary counseling regarding a low-salt diet. If values re- mained elevated, study-supplied lisinopril was initiated and ti- trated to achieve target goals according to a predetermined algorithm.2

Echocardiography Echocardiograms were performed in the last year of the study in 542 participants (of the 699 total randomized subjects) at

a median of ~4.5 years from diagnosis of T2D at an average age of 18 years, 2-6 years after randomization in TODAY as previously reported.4 The current cross-sectional analysis pres- ents data for those participants who had body composition and CRF measured within 6 months of the echocardiogram (n = 233), with a median duration between the echocardiogram measures and body composition/physical work capacity at a heart rate (HR) of 170 beats per minute (PWC-170) of 56 (0- 96) days. To describe in brief, M-mode and 2-dimensional (2D) measurements of LV and left atrial (LA) dimensions were per- formed and interpreted according to the guidelines of the American Society of Echocardiography at a core laboratory by the use of strict quality control procedures similar to those of the Coronary Artery Risk Development in Young Adults (ie, CARDIA) study.8,9 LV mass (g) = 0.80 × 1.04 ([VSTd + LVIDd + PWTd]3 – [LVIDd]3) + 0.6; all measurements in diastole, LV ejection fraction ([LV end diastolic volume − LV end systolic volume]/LV end diastolic volume; volumes calculated by the Simpson rule), and LV relative wall thickness ([LV posterior wall thickness in diastole × 2]/LV end diastolic diameter) were calculated from 2D directed M-mode images of the LV ac- cording to the recommendations of the American Society of Echocardiography.9 Tissue Doppler imaging analysis of the lateral mitral valve annulus during diastole was performed, and values from sequential beats were averaged; diastolic func- tion was defined as the ratio of early transmitral flow veloc- ity to early mitral annular velocity [E/Em].10 RV function was assessed by tricuspid annular plane systolic excursion (TAPSE).4

Body Composition Dual-energy x-ray absorptiometry (DXA) scans were per- formed at each clinical center according to study-specific guide- lines for subject positioning standardized across the different DXA systems, as reported previously.11

Cardiorespiratory Fitness CRF was assessed by a submaximal test with a cycle ergometry (818E bike; Quinton Monark, Seattle, Washington). Ob- served workload and HR were recorded up to 4 times at 60 rpm at 3-minute intervals.Workload at a HR of 170 beats per minute was estimated according to a best-fit equation. PWC-170 was calculated.5 Previous studies show that the PWC-170 is a valid indicator for predicting maximal oxygen uptake, the refer- ence measure for aerobic fitness.12,13

Statistical Analyses Descriptive statistics presented are percent or median, minimum, and maximum. Analysis of variance was used to compare participant characteristics across the 3 treatment groups. Correlation analyses were used to evaluate bivariate relationships. Regression models were used to assess relation- ships among echocardiography outcomes and independent pre- dictors, including age, sex, race-ethnicity, HbA1c, CRF, body composition measures, study treatment group, time on as- signed treatment, and cardiovascular risk factors (diagnosis of hypertension or BP medication use, smoking). We compared unindexed LV mass to body composition measures to be able

THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume 177

160 Bacha et al

to examine the individual association of body compartments with total LV mass. Serum lipids did not have an impact on cardiac structure and function in our previous analyses of the larger cohort4 and were therefore not included in the regres- sion models. All analyses are considered exploratory, with sta- tistical significance defined as P < .05 and no adjustment for multiple testing; the study was powered for the primary outcome only. All analyses were performed with SAS soft- ware (SAS Institute Inc, Cary, North Carolina).

Results

Patient enrollment started in July 2004 and ended in Febru- ary 2009. Participant characteristics, body composition, and CRF data are shown in Table I by treatment group. Subjects had a median age of 18.3 (min-max 12.4-24.2) years, 63% were female, with a median HbA1c of 6.8%. At the time of the echocardiogram, 109 of the 233 (~46%) participants reached primary outcome and needed chronic insulin treatment. Hy- pertension was diagnosed in 30.3% on the basis of BP values or a history of taking BP medications. Comparison of the analy- sis sample with the remaining 465 TODAY participants showed no significant differences for sex, race-ethnicity, HbA1c, treat- ment group assignment, or study outcome; however, the current study’s cohort was about a year younger (median age at ran-

domization of 13 [min-max 10-17] years vs 1410-18 years) and had overall lower BMI at end of study (33.4 [22.9-53.1] vs 36.7 [21.1-66.4] kg/m2), which may be a reflection of the fact that DXA studies were not technically possible in larger individuals.

Treatment was related to several important study variables in this analysis. When treatment groups were analyzed by ANOVA, BMI was lower in the M + L group compared with the M + R group (31.2 [22.9-47.6] kg/m2 in M + L vs 34.7 [23.8- 53.1] kg/m2 in M + R and vs 33.5 [23.4-47.0] kg/m2 in M, ANOVA P = .008). FM and LBM were 16% and 5% lower in the M + L group compared with the M + R group (11% and 5% lower in the M + L group compared with the M group), respectively, indicating possible effect of the lifestyle arm on body composition with relatively greater percentage of lean mass at a lower BMI in the M + L group.

Echocardiography Outcomes Echocardiography outcome data are provided in Table I by treatment group and further described by treatment group and sex in Table II. Median LV mass in this cohort was 139.0 g; indexed for height 34.8g/m2.7; ~90th percentile for the sex- specific population mean, and not significantly different across treatment groups.4,14 LV ejection fraction was in the normal range.Although ejection fraction was slightly lower in the M + R group, it was within the normal range in all 3 treatment arms. Sensitivity analysis in the larger TODAY cohort did not reveal

Table I. Participant characteristics at time of echocardiography: anthropometrics, body composition, CRF, and echocardiography measures

M (n = 79, 61% F)

M + R (n = 80, 69% F)

M + L (n = 74, 61% F) Adjusted P value

Age, y 18.8 (13.7-23.1) 18.0 (12.4-22.7) 18.2 (13.9-24.2) – Race .8362

Hispanic 28 (35%) 41 (51%) 35 (47%) NHB 28 (35%) 21 (26%) 18 (24%) NHW 19 (24%) 13 (16%) 15 (20%) Other 4 (5%) 5 (6%) 5 (7%)

HbA1c (%) 8.2 (4.8-14.1) 6.1 (4.3-14.7) 7.2 (4.6-15.1) .6126 Time in study, y 4.3 (2.0-7.2) 4.5 (2.1-6.7) 5.1 (2.1-7.2) – Reached PO 44 (56%) 29 (36%) 36 (49%) N/A* BMI, kg/m2 33.5 (23.4-47.0) 34.7 (23.8-53.1) 31.2 (22.9-47.6) .0147†

FM, kg 35.3 (16.1-62.6) 37.9 (17.8-70.7) 31.7 (10.8-59.1) .0032†

LBM, kg 58.6 (41.8-87.3) 58.6 (37.4-90.4) 55.4 (35.1-91.2) .0094‡

Percent body fat (%) 37.2 (21.0-51.9) 39.2 (20.2-52.7) 37.5 (13.8-49.4) .1993 Total cholesterol, mg/dL 157 (94-254) 157 (89-239) 159 (82-335) .4033 Triglycerides, mg/dL 105 (26-1783) 107 (35-548) 107.0 (44-1112) .2411 Systolic BP, mm Hg 117 (90-153) 112 (84-151) 112 (94-149) .3378 % with hypertension 32 (41%) 22 (28%) 15 (20%) – Cigarette use 9 (11%) 9 (11%) 10 (14%) – Insulin use 28 (24%) 27 (17%) 33 (23%) – PWC-170, kg/min 691 (225-1884) 716 (328-1958) 658 (317-1978) .2556 LV mass (g)/ height (m)2.7 35.6 (22.3-60.8) 34.7 (19.1-57.4) 32.9 (18.1-73.8) .8259 LV ejection fraction (%) 69.3 (47.5-83.1) 66.1 (52.9-78.1) 68.5 (47.1-83.0) .0045§

TAPSE, cm 2.1 (1.3-2.8) 2.2 (1.4-3.4) 2.1 (1.1-3.4) .1617 Wall thickness 0.32 (0.24-0.56) 0.32 (0.22-0.58) 0.32 (0.25-0.60) .2173 E/Em ratio 5.8 (2.8-12.5) 5.1 (2.1-9.2) 6.2 (2.6-12.4) .0079§

F, female; N/A, not available; NHB, non-Hispanic black; NHW, non-Hispanic white; PO, primary outcome. Data are median (min-max). P values adjusted for sex, baseline age, hypertension, number cigarettes/d, time in study, and insulin use. Thus, P values not given for age, time in study, % with hypertension, cigarette use, or insulin use. *Model fit is questionable; no P-value obtained. †M + L significantly different from M + R. ‡M + L significantly different from M and M + R. §M + R is significantly different from M and M + L.

October 2016 ORIGINAL ARTICLES

161Relationship of Cardiac Structure and Function to Cardiorespiratory Fitness and Lean Body Mass in Adolescents and Young Adults with Type 2 Diabetes

a relationship between treatment modality and ejection frac- tion. LA internal diameter was not significantly different among the 3 groups. LV diastolic function (E/Em) was slightly lower in the M + R group compared with the other 2 groups (P = .007). Median TAPSE was 2.1 (1.1-3.4) cm, within normal limits and not significantly different among the 3 treatment groups.

Relationship of Cardiac Structure and Function Measures to Body Composition and CRF LV mass was positively related to LBM (r = 0.7, P < .001) and less strongly to FM (r = 0.2, P = .0072). LV mass correlated posi- tively with CRF (r = 0.5, P < .001). This relationship per- sisted after we adjusted for FM (r = 0.54, P < .001) but weakened after we adjusted for LBM (r = 0.2, P = .0045) (Figure 1, A). These relationships persisted after adjustment for treatment group effect (Figure 1, A). Similar relationships of LV inter- nal dimension with CRF and body composition measures were observed. LV relative wall thickness was related positively to LBM (r = 0.2, P = .003) but not to FM or CRF despite a trend towards lower relative wall thickness with greater fitness (P < .10). LA internal diameter correlated positively with LBM (r = 0.3, P < .001), FM (r = 0.4, P < .0001), and CRF (r = 0.2, P = .0033).

LV ejection fraction was not related to body composition measures or to CRF. LV (E/Em), however, was positively related to FM (r = 0.14, P = .03) and % body fat (r = 0.18, P = .007) and negatively related to % LBM (r = −0.18, P = .007) but not total lean mass or CRF (r = −0.117, P = .08).

TAPSE was positively related to LBM (r = 0.13, P < .05) and to CRF (r = 0.2, P = .0014) but not to FM (Figure 1, B). The relationship between TAPSE and CRF weakened after we ad- justed for LBM (r = 0.17, P = .012), but not after we adjusted for FM (r = 0.22, P = .0009). The relationship among TAPSE, LBM, and CRF persisted after we adjusted for treatment group (Figure 1, B).

LV Mass, E/Em Ratio, and RV Functional Outcomes and Cardiovascular Disease Risk Factors Because of the strong relationships of LV mass and TAPSE to LBM and physical fitness, regression models were run with LV

mass and TAPSE as the dependent variables and as covariates: treatment group, race-ethnicity, sex, age, LBM, PWC 170, HbA1c, hypertension, number of cigarettes per day, and time participation in the study. For LV mass, LBM and PWC 170 (P < .0001 and P = .0081, respectively) remained significant in the fully adjusted models. The slope estimate for LBM was 2.13 (95% CI 1.66-2.60), indicating that, for every 1-kg increase in LBM, LV mass increased by 2.13 units on average. The slope estimate for PWC 170 was 0.023 (95% CI 0.006-0.040) (Figure 2, A). PWC 170 and HbA1c (P = .0187 and P = .0142, respectively) were significant predictors of TAPSE. The slope estimate for PWC 170 was 0.0002 (95% CI 0.00004-0.0005). The slope estimate for HbA1c was −0.022 (95% CI −0.039 to −0.004), indicating that lower HbA1c was associated with better RV function (Figure 2, B).With E/Em as the dependent vari- able, and FM instead of LBM as an independent variable in the above regression model, treatment group (P = .0016) and FM (P = .023) contributed significantly to the variance in E/Em.

Discussion

We evaluated the relationship of CRF and body composition to cardiac structure and function in older adolescents with T2D from the TODAY study. We demonstrate that, in this group of obese youth with T2D, LV mass is positively related to CRF and to LBM, LV diastolic function is greater (worse) with greater FM, RV function (TAPSE) is positively related to CRF and nega- tively related to HbA1c, and ejection fraction is unrelated to body composition or CRF.

Studies of the relationship between physical fitness and cardiac structure and function have been performed previ- ously in athletes. These generally have been performed to show the impact of training on heart size and function or to dem- onstrate differences between athletes and nonathletes with regard to cardiac function to better characterize the athlete’s heart.15-17 Generally these studies show that physical training or greater fitness is associated with a LV mass increase of about 10% and normal cardiac systolic function without adverse changes in cardiac geometry. Diastolic function often is en- hanced with training. Fat free mass and not FM predicts LV mass and LV end-diastolic dimension in endurance athletes

Table II. Echocardiography measures (median [min-max] or mean [SD]) by treatment group and sex

Outcomes

Female Male

M M + R M + L M M + R M + L

LV mass, g* 134 (76-205) 129 (74-204) 117 (79-182) 178 (102-269) 166 (91-314) 158 (105-364) LV mass/height,2.7 (g/m2.7)* 34.5 (22.3-49.8) 33.5 (19.1-52.8) 32.4 (18.1-50.2) 39.4 (27.7-60.8) 37.7 (23.2-57.4) 36.1 (24.8-73.8) LV relative wall thickness 0.31 (0.24-0.50) 0.32 (0.22-0.58) 0.31 (0.25-0.54) 0.34 (0.27-0.56) 0.32 (0.25-0.45) 0.33 (0.25-0.60) LV fractional shortening (%) 38.9 (4.7) 36.6 (4.7) 39.5 (5.0) 40.2 (6.2) 37.2 (4.4) 36.60 (5.8) LA internal dimension, cm* 3.5 (0.4) 3.6 (0.5) 3.37 (0.46) 3.6 (0.40) 3.7 (0.4) 3.6 (0.5) LA internal dimension/height, cm/m 2.1 (0.2) 2.2 (0.3) 2.1 (0.3) 2.1 (0.2) 2.1 (0.2) 2.1 (0.3) TAPSE, cm 2.1 (0.3) 2.2 (0.4) 2.1 (0.4) 2.1 (0.4) 2.2 (0.3) 2.1 (0.4) Doppler diastology LV E, cm/s* 96.8 (20.6) 90.6 (14.9) 99.3 (20.6) 88.8 (19.1) 87.9 (18.0) 89.5 (14.7) LV Em, cm/s 16.6 (4.1) 17.7 (4.1) 16.3 (3.7) 16.6 (5.0) 17.1 (4.5) 17.39 (6.5) E/Em ratio 6.2 (1.9) 5.4 (1.4) 6.4 (1.8) 5.8 (1.8) 5.3 (1.2) 5.8 (2.4)

*Female subjects significantly different from male subjects, P < .05.

THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume 177

162 Bacha et al

and age-matched control adults.18 TAPSE has been studied in women playing recreational soccer and improved with training.19 This finding is consistent with our results showing an association of TAPSE with greater fitness. A study of 8- to 12-year-old obese children, however, did not show an asso- ciation of improvement in conditioning with TAPSE.20

In contrast, there are limited data linking measures of physi- cal performance and body composition to measures of cardiac structure and function in overweight/obese youth and very limited information is available in youth with T2D. Our find- ings of a positive relationship between LV mass and CRF and LBM suggest that part of the increase in LV mass in obese youth with T2D is a healthy adaptation to allow adequate heart func- tion that meets the demands of a heavier individual for physi- cal performance, while maintaining a normal ejection fraction. Our results are consistent with observations from Gidding et

al,21 who studied a cohort of obese adolescents with BMI > 40 kg/m2 and assessed physical fitness by oxygen con- sumption at maximal effort. In these adolescents, a strong and independent relationship of fitness to LV mass was noted (Gidding SS, Nehgme R, Heise C, Muscar C, Linton A, Hassink S, unpublished data). Body composition was not assessed in that study. Mitchell et al studied cardiac structure and func- tion in relation to visceral fat and FM, and showed a positive relationship of FM to LV mass and a positive correlation of fitness to LV mass/height.2,7,22 However, these investigators did not report LBM, did not directly examine the independent effects of fitness and LBM in their cohort, and, by indexing LV mass, obscured the relationship to LBM. Rosiglitazone in- creases FM as a consequence of treatment; this was observed in the TODAY cohort.1 We adjusted for treatment assign- ment in this analysis and an independent effect of rosiglitazone

r=0.7, p<0.001 Adjusted for treatment group, r=0.73, p<0.0001

r=0.5, p<0.001 Adjusted for FM, r=0.54, p<0.001

Adjusted for LBM, r=0.2, p=0.0045 Adjusted for treatment group, r=0.52, p<0.0001

r=0.2, p=0.0014 Adjusted for FM, r=0.22, p=0.0009 Adjusted for LBM, r=0.17, p=0.012

Adjusted for treatment group, r=0.21, p=0.0014

r=0.13, p<0.05 Adjusted for treatment group, r=0.14, p=0.038

A

B

Figure 1. Relationship of LBM and CRF to A, LV mass; and B, RV function (TAPSE).

October 2016 ORIGINAL ARTICLES

163Relationship of Cardiac Structure and Function to Cardiorespiratory Fitness and Lean Body Mass in Adolescents and Young Adults with Type 2 Diabetes

independent of FM assessed by DXA on outcomes was not observed.

Our findings are highly supportive of the findings of Daniels et al,6 which show a stronger relationship of LBM than FM to LV mass, and by the findings from the Strong Heart study in

adults,23 which show that LBM is a stronger determinant of cardiac output than FM after several cardiovascular disease risk factors are adjusted. It is important to remember that to achieve a given level of fitness, obese individuals do more physical work than their lean counterparts because of the need to support

35.11

53.82 72.53

91.24

Total lean body mass (kg) 225

809

1393

1978

Maximal workload at HR 170 in kgm/min88

143

197

252

Predicted LV mass

β=0.023, p=0.008

β=2.13, p<0.0001

Met + Rosi Met + TLP Met only

4.3

7.9 11.5

15.1

HBA1C 225

809

1393

1978

Maximal workload at HR 170 in kgm/min1.799

2.044

2.289

2.533

Predicted TAPSE

β=0.0002, p=0.0187

β=-0.022, p=0.0142

Met + Rosi Met + TLP Met only

A

B

Figure 2. A, 3-dimensional plot of the joint distribution of LBM, CRF, and LV mass; and B, 3-dimensional plot of the joint dis- tribution of HbA1c, CRF, and RV function. The b values represent the estimate of the slope of the regression equation.

THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume 177

164 Bacha et al

greater physical weight.24 This added effort naturally varies de- pending on the type of exercise and the need for weight support. It is likely that the increased expenditure of energy to perform a specific amount of work in an obese individual requires greater cardiac work and thus leads to cardiac adaptation at lower levels of fitness than for lean individuals.

Although LV mass is strongly related to cardiovascular out- comes (including cardiovascular death, ischemic heart disease, heart failure, peripheral arterial disease, and stroke), the re- lationship may not be linear.25,26 In the CARDIA study, a lon- gitudinal study of cardiovascular risk evolution in young adults, both LV mass and Framingham risk score predicted cardio- vascular outcomes.26 The prevalence of adverse cardiovascu- lar outcomes, however, did not increase until LV mass was greater than the 85th percentile. Further, risk reclassification based on adding LV mass measurement to the Framingham risk score was significantly better for cardiovascular event risk prediction in lean than obese individuals.

There is limited information on the relationship between LA size and fitness. In general, greater fitness is associated with greater LA size both in the general population and in fit hand- ball athletes.27,28 Interestingly, increases in LA size are only as- sociated with poorer diastolic function in nonathletes.28 Our data suggest that, in obese adolescents with T2D, FM is the strongest correlate of LA size, but lean mass and fitness also contribute. Because FM was associated with poorer diastolic function, it can be hypothesized that LA size is increased by either worse diastolic function associated with obesity or by a larger heart size required for physical performance. In- crease in LA size has been reported in obese American Indian adolescents with a high prevalence of metabolic syndrome (50%) in the Strong Heart study.29 The obese group also ex- hibited increased LA systolic force with normal LV filling pres- sure, interpreted to reflect some diastolic dysfunction. Relationship to body composition to LA size and function was not evaluated in that study.

In the current study, E/Em ratio from tissue Doppler imaging was used as the measure of diastolic function. In contrast to LV mass, diastolic function was associated most strongly with FM, and this relationship was adverse in that greater FM was associated with a greater E/Em ratio. There was a trend sug- gesting greater fitness or lean mass was associated with a lower ratio, but these relationships did not reach statistical signifi- cance. Also, the effect is small and values are well within the normal range; therefore, the clinical significance of this dif- ference is uncertain. There is limited information on the impact of fitness or training on this measure. In obese adolescents, one study showed no change in E/Em ratio with short-term exercise training,30 whereas another small study reported im- provement in systolic and diastolic function after 3 months of aerobic training, which was more evident when evaluated by an exercise stress echocardiogram.31 Nadeau et al32 did not find a difference in E/Em in a relatively small group of youth with T2D compared with obese and normal weight controls despite reduced maximal exercise capacity in the youth with T2D com- pared with the other 2 groups. An effect of treatment group on E/Em ratio was noted; however, there was no consistent

effect of treatment on E/Em ratio and other measures of heart function in the larger cohort as assessed by sensitivity analy- ses looking at duration of exposure to treatment and echocardiographic outcomes.4

There are some limitations to this study. The subset of TODAY participants evaluated for this study was younger and had lower BMI than the remaining TODAY cohort, mainly because of the technical difficulties of obtaining DXA scans in larger individuals. These adolescents may, therefore, have better overall body composition and CRF than the rest of the T2D cohort. There was a time interval of as much as 6 months (median 56 days) between echocardiograms and other mea- sures in the study. This may have a small impact on results, but in general TODAY participants did not have significant changes in BMI or physical activity level or physical fitness during the course of the study. Because of the severe obesity of the cohort, 2D echo measures such as LA area and volume had low reproducibility and thus were not analyzed. More adverse cardiac structural and functional abnormalities may thus have been missed in the youth with severe obesity. Some correlations are small, suggesting a limited effect, particu- larly for RV function and LV diastolic function. However, par- ticipants in this study were adolescents with a relatively short duration of diabetes, which may explain the lack of a more pro- nounced effect of dysglycemia. We did not adjust for mul- tiple comparisons. Nevertheless, our findings are still relevant to the majority of youth with obesity and T2D. The availabil- ity of a normal-weight and a more-fit control group would have been desirable and may have strengthened our findings. The study is cross-sectional, but planned follow-up of the cohort, including an echocardiogram, will further evaluate the long- term implications of our findings.

In conclusion, despite a high prevalence of obesity and hy- pertension and an overall low level of fitness in obese youth with T2D, cardiac adaptations to fitness and LBM explain sub- stantial variability in LV mass and RV function. For LV mass, this positive association suggests that part of the increase in LV mass may be adaptive to greater body size needs. For RV function, greater fitness may counteract adverse effects of poor glycemic control.

Longitudinal follow-up of these youth will help us under- stand the implications of the observed increase in LV mass and the long-term effect on LV function and RV function, and the effects of glycemic control and cardiovascular disease risk factors on these variables. Our findings are supportive of promoting measures to improve CRF in individuals with T2D as it may offset some of the adverse effects of diabetes on cardiac function. ■

We gratefully acknowledge the participation and guidance of the Ameri- can Indian partners associated with the clinical center located at the Uni- versity of Oklahoma Health Sciences Center, including members of the Absentee Shawnee Tribe, Cherokee Nation, Chickasaw Nation, Choctaw Nation of Oklahoma, and Oklahoma City Area Indian Health Service. Materials developed and used for the TODAY standard diabetes edu- cation program and the intensive lifestyle intervention program are avail- able to the public at https://today.bsc.gwu.edu/.

October 2016 ORIGINAL ARTICLES

165Relationship of Cardiac Structure and Function to Cardiorespiratory Fitness and Lean Body Mass in Adolescents and Young Adults with Type 2 Diabetes

Submitted for publication Feb 22, 2016; last revision received May 18, 2016; accepted Jun 13, 2016

Reprint requests: Laura Pyle, PhD, Department of Pediatrics, School of Medicine, University of Colorado Denver Anschutz Medical Campus, AMC Building 406, Mail Stop B119-406, 12477 E 19th Ave, Aurora, CO 80045. E-mail: laura.pyle@ucdenver.edu

References 1. Group TS, Zeitler P, Hirst K, Pyle L, Linder B, Copeland K, et al. A clini-

cal trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med 2012;366:2247-56.

2. Group TS. Lipid and inflammatory cardiovascular risk worsens over 3 years in youth with type 2 diabetes: the TODAY clinical trial. Diabetes Care 2013;36:1758-64.

3. Group TS. Rapid rise in hypertension and nephropathy in youth with type 2 diabetes: the TODAY clinical trial. Diabetes Care 2013;36:1735-41.

4. Levitt Katz L, Gidding SS, Bacha F, Hirst K, McKay S, Pyle L, et al. Al- terations in left ventricular, left atrial, and right ventricular structure and function to cardiovascular risk factors in adolescents with type 2 diabe- tes participating in the TODAY clinical trial. Pediatr Diabetes 2015;16:39- 47.

5. Kriska A, Delahanty L, Edelstein S, Amodei N, Chadwick J, Copeland K, et al. Sedentary behavior and physical activity in youth with recent onset of type 2 diabetes. Pediatrics 2013;131:e850-6.

6. Daniels SR, Kimball TR, Morrison JA, Khoury P, Witt S, Meyer RA. Effect of lean body mass, fat mass, blood pressure, and sexual maturation on left ventricular mass in children and adolescents. Statistical, biological, and clinical significance. Circulation 1995;92:3249-54.

7. Sivanandam S, Sinaiko AR, Jacobs DR Jr, Steffen L, Moran A, Steinberger J. Relation of increase in adiposity to increase in left ventricular mass from childhood to young adulthood. Am J Cardiol 2006;98:411-5.

8. Armstrong AC,Ricketts EP,Cox C,Adler P,Arynchyn A,Liu K,et al. Quality control and reproducibility in M-Mode, two-dimensional, and speckle tracking echocardiography acquisition and analysis: the CARDIA study, year 25 examination experience. Echocardiography 2015;32:1233-40.

9. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and theEuropeanAssociationof CardiovascularImaging.JAmSocEchocardiogr 2015;28:1-39.e14.

10. Mor-Avi V,Lang RM,Badano LP,Belohlavek M,Cardim NM,Derumeaux G, et al. Current and evolving echocardiographic techniques for the quan- titative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography. J Am Soc Echocardiogr 2011;24:277-313.

11. Group TS. Treatment effects on measures of body composition in the TODAY clinical trial. Diabetes Care 2013;36:1742-8.

12. Boreham CA, Paliczka VJ, Nichols AK. A comparison of the PWC170 and 20-MST tests of aerobic fitness in adolescent schoolchildren. J Sports Med Phys Fitness 1990;30:19-23.

13. McMurray RG, Guion WK, Ainsworth BE, Harrell JS. Predicting aerobic power in children.A comparison of two methods.J Sports Med Phys Fitness 1998;38:227-33.

14. Daniels SR, Loggie JM, Khoury P, Kimball TR. Left ventricular geometry and severe left ventricular hypertrophy in children and adolescents with essential hypertension. Circulation 1998;97:1907-11.

15. Utomi V, Oxborough D, Whyte GP, Somauroo J, Sharma S, Shave R, et al. Systematic review and meta-analysis of training mode, imaging modality and body size influences on the morphology and function of the male athlete’s heart. Heart 2013;99:1727-33.

16. Baggish AL, Wang F, Weiner RB, Elinoff JM, Tournoux F, Boland A, et al. Training-specific changes in cardiac structure and function: a prospec- tive and longitudinal assessment of competitive athletes. J Appl Physiol 2008;104:1121-8.

17. Venckunas T, Mazutaitiene B. The role of echocardiography in the dif- ferential diagnosis between training induced myocardial hypertrophy versus cardiomyopathy. J Sports Sci Med 2007;6:166-71.

18. Whalley GA, Doughty RN, Gamble GD, Oxenham HC, Walsh HJ, Reid IR, et al. Association of fat-free mass and training status with left ven- tricular size and mass in endurance-trained athletes. J Am Coll Cardiol 2004;44:892-6.

19. Randers MB, Andersen LJ, Orntoft C, Bendiksen M, Johansen L, Horton J, et al. Cardiovascular health profile of elite female football players com- pared to untrained controls before and after short-term football train- ing. J Sports Sci 2013;31:1421-31.

20. Hansen PR, Andersen LJ, Rebelo AN, Brito J, Hornstrup T, Schmidt JF, et al. Cardiovascular effects of 3 months of football training in over- weight children examined by comprehensive echocardiography: a pilot study. J Sports Sci 2013;31:1432-40.

21. Gidding SS, Nehgme R, Heise C, Muscar C, Linton A, Hassink S. Severe obesity associated with cardiovascular deconditioning, high prevalence of cardiovascular risk factors, diabetes mellitus/hyperinsulinemia, and re- spiratory compromise. J Pediatr 2004;144:766-9.

22. Mitchell BM, Gutin B, Kapuku G, Barbeau P, Humphries MC, Owens S, et al. Left ventricular structure and function in obese adolescents: rela- tions to cardiovascular fitness, percent body fat, and visceral adiposity, and effects of physical training. Pediatrics 2002;109:E73-3.

23. Collis T, Devereux RB, Roman MJ, de Simone G, Yeh J, Howard BV, et al. Relations of stroke volume and cardiac output to body composition: the strong heart study. Circulation 2001;103:820-5.

24. Norman AC, Drinkard B, McDuffie JR, Ghorbani S, Yanoff LB, Yanovski JA. Influence of excess adiposity on exercise fitness and performance in overweight children and adolescents. Pediatrics 2005;115:e690-6.

25. Armstrong AC, Gidding S, Gjesdal O, Wu C, Bluemke DA, Lima JA. LV mass assessed by echocardiography and CMR, cardiovascular outcomes, and medical practice. JACC Cardiovasc Imaging 2012;5:837-48.

26. Armstrong AC, Jacobs DR Jr, Gidding SS, Colangelo LA, Gjesdal O, Lewis CE, et al. Framingham score and LV mass predict events in young adults: CARDIA study. Int J Cardiol 2014;172:350-5.

27. Dzudie A, Menanga A, Hamadou B, Kengne AP, Atchou G, Kingue S. Ultrasonographic study of left ventricular function at rest in a group of highlytrainedblackAfricanhandballplayers.EurJEchocardiogr2007;8:122- 7.

28. Nistri S, Galderisi M, Ballo P, Olivotto I, D’Andrea A, Pagliani L, et al. Determinants of echocardiographic left atrial volume: implications for normalcy. Eur J Echocardiogr 2011;12:826-33.

29. Chinali M, de Simone G, Roman MJ, Lee ET, Best LG, Howard BV, et al. Impact of obesity on cardiac geometry and function in a population of adolescents: the Strong Heart Study. J Am Coll Cardiol 2006;47:2267- 73.

30. Millen A, Norton G, Avidon I, Woodiwiss A. Effects of short-term exer- cise training on tissue Doppler indices of left ventricular diastolic function in overweight and obese individuals. J Sports Sci 2014;32:487- 99.

31. Ingul CB, Tjonna AE, Stolen TO, Stoylen A, Wisloff U. Impaired cardiac function among obese adolescents: effect of aerobic interval training.Arch Pediatr Adolesc Med 2010;164:852-9.

32. Nadeau KJ, Zeitler PS, Bauer TA, Brown MS, Dorosz JL, Draznin B, et al. Insulin resistance in adolescents with type 2 diabetes is associated with impaired exercise capacity. J Clin Endocrinol Metab 2009;94:3687- 95.

THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume 177

166 Bacha et al

Appendix 1

Additional members and institutes of the TODAY Study Group include (*indicates principal investigator or director):

Clinical Centers—Baylor College of Medicine: S. McKay*, M. Haymond*, B. Anderson, C. Bush, S. Gunn, H. Holden, S. M. Jones, G. Jeha, S. McGirk, S. Thamotharan; Case Western Reserve University: L. Cuttler*, E. Abrams, T. Casey, W. Dahms (deceased), C. Ievers-Landis, B. Kaminski, M. Koontz, S. MacLeish, P. McGuigan, S. Narasimhan; Children’s Hospital Los Angeles: M. Geffner*, V. Barraza, N. Chang, B. Conrad, D. Dreimane, S. Estrada, L. Fisher, E. Fleury-Milfort, S. Hernan- dez, B. Hollen, F. Kaufman, E. Law, V. Mansilla, D. Miller, C. Muñoz, R. Ortiz, A. Ward, K. Wexler, Y.K. Xu, P. Yasuda; Chil- dren’s Hospital of Philadelphia: R. Berkowitz, S. Boyd, B. Johnson, J. Kaplan, C. Keating, C. Lassiter, T. Lipman, G. McGinley, H. McKnight, B. Schwartzman, S. Willi; Chil- dren’s Hospital of Pittsburgh: S. Arslanian*, S. Foster, B. Galvin, T. Hannon, I. Libman, M. Marcus, K. Porter, T. Songer, E. Venditti; Columbia University Medical Center: R. Goland*, D. Gallagher, P. Kringas, N. Leibel, D. Ng, M. Ovalles, D. Seidman; Joslin Diabetes Center: L. Laffel*, A. Goebel-Fabbri, M. Hall, L. Higgins, J. Keady, M. Malloy, K. Milaszewski, L. Rasbach; Mas- sachusetts General Hospital: D.M. Nathan*, A. Angelescu, L. Bissett, C. Ciccarelli, L. Delahanty, V. Goldman, O. Hardy, M. Larkin, L. Levitsky, R. McEachern, D. Norman, D. Nwosu, S. Park-Bennett, D. Richards, N. Sherry, B. Steiner; Saint Louis University: S. Tollefsen*, S. Carnes, D. Dempsher, D. Flomo, T. Whelan, B. Wolff; State University of New York Upstate Medical University: R. Weinstock*, D. Bowerman, S. Bristol, J. Bulger, J. Hartsig, R. Izquierdo, J. Kearns, R. Saletsky, P. Trief; University of Colorado Denver: P. Zeitler* (Steering Commit- tee Chair), N. Abramson, A. Bradhurst, N. Celona-Jacobs, J. Higgins, M. M. Kelsey, G. Klingensmith, T. Witten; Univer- sity of Oklahoma Health Sciences Center: K. Copeland* (Steer- ing Committee Vice-Chair), E. Boss, R. Brown, J. Chadwick, L. Chalmers, S. Chernausek, A. Hebensperger, C. Macha, R. Newgent, A. Nordyke, D. Olson, T. Poulsen, L. Pratt, J. Preske, J. Schanuel, S. Sternlof; University of Texas Health Science Center at San Antonio: J. Lynch*, N. Amodei, R. Barajas, C. Cody, D. Hale, J. Hernandez, C. Ibarra, E. Morales, S. Rivera, G. Rupert, A. Wauters; Washington University in St Louis: N. White*, A. Arbeláez, D. Flomo, J. Jones, T. Jones, M. Sadler, M. Tanner, A. Timpson, R. Welch; Yale University: S. Caprio*, M. Grey, C. Guandalini, S. Lavietes, P. Rose, A. Syme, W. Tamborlane.

Coordinating Center—George Washington University Bio- statistics Center: K. Hirst*, S. Edelstein, P. Feit, N. Grover, C. Long.

Project Office—National Institute of Diabetes and Diges- tive and Kidney Diseases: B. Linder*

Central Units—Central Blood Laboratory (Northwest Lipid Research Laboratories, University of Washington): S. M. Marcovina*, J. Harting; DEXA Reading Center (University of California at San Francisco): J. Shepherd*, B. Fan, L. Marquez, M. Sherman, J. Wang; Diet Assessment Center (University of South Carolina): M. Nichols*, E. Mayer-Davis, Y. Liu; Echocardiogram Reading Center (Johns Hopkins Univer- sity): J. Puccella, E. Ricketts; Fundus Photography Reading Center (University of Wisconsin): R. Danis*, A. Domalpally, A. Goulding, S. Neill, P. Vargo; Lifestyle Program Core (Wash- ington University): D. Wilfley*, D. Aldrich-Rasche, K. Frank- lin, C. Massmann, D. O’Brien, J. Patterson, T. Tibbs, D. Van Buren.

Other—Hospital for Sick Children, Toronto: M. Palmert; Medstar Research Institute, Washington DC: R. Ratner; Texas Tech University Health Sciences Center: D. Dremaine; Uni- versity of Florida: J. Silverstein.

Appendix 2

Funded by The National Institute of Diabetes and Digestive and Kidney Diseases and the National Institutes of Health Office of the Director (U01-DK61212, U01-DK61230, U01-DK61239, U01-DK61242, and U01-DK61254); the National Center for Research Resources General Clinical Research Centers (M01- RR00036 [to Washington University School of Medicine], M01-RR00043-45 [to Children’s Hospital Los Angeles], M01- RR00069 [to University of Colorado Denver], M01-RR00084 [to Children’s Hospital of Pittsburgh], M01-RR01066 [to Mas- sachusetts General Hospital], M01-RR00125 [to Yale Univer- sity], and M01-RR14467 [to University of Oklahoma Health Sciences Center]); and the National Center for Research Resources Clinical and Translational Science Awards (UL1- RR024134 [to Children’s Hospital of Philadelphia], UL1- RR024139 [to Yale University], UL1-RR024153 [to Children’s Hospital of Pittsburgh], UL1-RR024989 [to Case Western Reserve University], UL1-RR024992 [to Washington Univer- sity in St Louis], UL1-RR025758 [to Massachusetts General Hospital], and UL1-RR025780 [to University of Colorado Denver]).

October 2016 ORIGINAL ARTICLES

166.e1Relationship of Cardiac Structure and Function to Cardiorespiratory Fitness and Lean Body Mass in Adolescents and Young Adults with Type 2 Diabetes