Patients

Children with FH were prospectively enrolled in our pediatric department. Inclusion criteria were (1) the presence of one parent with a definite clinical or molecular diagnosis of FH, (2) age between 6 and 16 years, (3) use of a low-fat diet for ≥3 months, (4) fasting plasma LDL cholesterol levels above the 90th percentile and triglyceride levels <4.0 mmol/L on 2 separate occasions, (5) fasting glucose levels in the normal range, (6) adequate contraception (for sexually active girls); and (7) no treatment for hypercholesterolemia, including plant sterol or stanol.

We also studied control healthy children, who were matched 1:1 for age and were comparable for gender, recruited from the community with no family histories of hypercholesterolemia, hypertension, or obesity. The control subjects were recruited in Naples, Italy, and selected from asymptomatic children who were investigated for innocent heart murmurs. None of the control subjects had cardiovascular structural or functional abnormalities or received any medications. None of the selected patients with FH was excluded from the study. In all, we studied 90 children (45 with FH and 45 controls). The study protocol was approved by our local ethics committee. Written informed consent was obtained from both parents for all study subjects.

Clinical Assessment

Resting blood pressure was measured three times at all extremities using an automatic oscillometric cuff device (Dinamap; Critikon, Inc., Tampa, FL). On the monitoring day, the study nurses measured the office blood pressure three times consecutively, after the subjects had rested in the sitting position for ≥5 min. Hypertension was defined when office blood pressure was above the 90th percentile for age, sex, and height.

Ambulatory Blood Pressure Monitoring

A SpaceLabs model 90207 monitor (SpaceLabs, Inc., Redmond, WA) weighing 340 g (including batteries) was used. Our methodology for ambulatory blood pressure monitoring studies has already been described.

Standard Echocardiographic Evaluation

LV measurements were taken from two-dimensional guided M-mode tracings. LV mass indexed for height ^2.7 and body surface area was calculated using the Devereux-modified American Society of Echocardiography cube equation. LV end-diastolic and end-systolic volumes and resting LV ejection fraction were computed from two-chamber and four-chamber views, using a modified Simpson’s biplane method. In all patients with FH, the LV outflow tract was evaluated, and none showed obstruction (defined as peak gradient ≥15 mm Hg). Using pulsed-wave Doppler, mitral inflow velocities, peak early diastolic velocity, peak late diastolic velocity, their ratio, and early diastolic wave deceleration time were measured. Myocardial velocities were obtained from the apical window to minimize the effect of cardiac translation. A 3-mm sample volume was placed at the lateral mitral annulus. The resulting myocardial velocities were recorded for at least five satisfactory cardiac cycles were obtained. The peak velocities at the lateral annulus during early diastole were measured. The ratio of peak transmitral early velocity to early diastolic mitral annular velocity was calculated.

STE

An ultrasound system (Vivid 7; GE Vingmed Ultrasound AS, Horten, Norway) with an M3S probe was used for the speckle-tracking study. Second-harmonic B-mode images of apical three-chamber, four-chamber, and two-chamber views and parasternal short-axis views at the level of the mitral valve, papillary muscles, and at the apical level were obtained and digitally stored in cine-loop format for offline analysis (EchoPAC PC version 6.0.0; GE Vingmed Ultrasound AS) ( Figure 1 ). The frame rate was 75 ± 16 frames/sec. After selecting the best-quality two-dimensional image of the cardiac cycle, the LV endocardial border was manually traced at the end-systolic frame, from which a speckle-tracking region of interest was automatically selected to approximate the myocardium between the endocardium and epicardium. The width of the region of interest was adjusted as needed to accommodate the total thickness of the LV wall. The computer automatically tracked stable objects in each frame using the sum of absolute differences algorithm, which is verified by the computer; LV segments with verification were used for further analysis. The workstation then computed and generated strain curves. The software automatically divided the cross-sectional image into six segments, which were named and identified according to the statement of the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. The LV segments to be analyzed were the apical, mid, and basal segments of the septal, lateral, inferior, anterior, anteroseptal, and posterolateral walls of the apical views. In the parasternal views, the basal, mid, and apical segments of the anteroseptal, anterior, lateral, posterior, inferior, and septal walls were studied. Strain curves of three consecutive cardiac cycles and values were imported for further analysis. Cardiac cycles with lengths >10% different from the mean length of the three cardiac cycles were excluded from averaging and thus from further analysis. Myocardial longitudinal, radial, and circumferential strain values were obtained. To determine global longitudinal strain, the strain values of the 18 segments were averaged for the apical views. To determine average circumferential and radial strains, the strain values of the 18 segments were averaged for the short-axis views.

(A) Longitudinal strain was obtained from the apical views. (B) Circumferential strain was obtained from the parasternal short-axis views. (C) Radial deformation was obtained from the same parasternal short-axis views. Note the presence of reduced circumferential deformation in (B) and increased radial deformation in (C) .

Statistical Analysis

StatView software (SAS Institute Inc., Cary, NC) was used for statistical analysis to calculate the mean, standard deviation, distribution, and normal plots of the variables studied. Univariate analysis of continuous variables was performed using unpaired Student’s t tests and Mann-Whitney U tests. Dichotomous variables were analyzed using 2 × 2 tables and χ ² tests (using the Cochran-Mantel-Haenszel method). Linear regression analysis was performed to study the relation between strain and continuous variables (total cholesterol, LDL cholesterol, age, and LV mass indexed for height ^2.7 and for body surface area). The null hypothesis was rejected for a P value < .05.

Reproducibility was determined in 20 randomly selected patients. Interobserver and intraobserver variability was examined using both Pearson’s bivariate two-tailed correlations and Bland-Altman analysis. Correlation coefficients, 95% confidence limits, and percentage errors (calculated as the difference between the two measurements divided by the mean value of the two measurements) were reported.

Standard Echographic Evaluation

Children with FH showed thicker LV walls and significantly increased LV mass indexed for height ^2.7 ( P = .0008) and for body surface area ( P < .0001) than controls ( Table 2 ). Global systolic function as expressed by ejection fraction was similar for both groups. Assessment of diastolic function demonstrated significant prolongation of mitral inflow deceleration time ( P < .0001), a reduction of early diastolic mitral annular velocity ( P < .0001), and higher transmitral early/early diastolic mitral annular velocity ratios ( P = .0003) in children with FH. Intima-media thickness was also significantly increased in children with FH ( P = .001).

STE

Longitudinal ( Table 3 ) and circumferential ( Table 4 ) myocardial deformation of the left ventricle was significantly reduced in children with FH. Radial deformation ( Table 5 ) was increased in children with FH ( Figure 2 ). A significant inverse correlation was found between LDL cholesterol levels and longitudinal strain ( R = 0.48, P = .001). A significant correlation was also noted between LDL cholesterol levels and radial strain ( R = 0.41, P = .01) ( Figure 3 ).

Table 4

Circumferential strain in the study subjects

Circumferential strain (%)	Children with FH ( n = 45)	Controls ( n = 45)	P
Mitral valve level
Anteroseptal wall	−23.6 ± 4.9	−28.6 ± 6.4	.02
Anterior wall	−18.6 ± 6.1	−21.4 ± 6	.03
Lateral wall	−17.6 ± 4.7	−19.1 ± 6.8	.23
Posterior wall	−15.2 ± 7.1	−18.1 ± 5.7	.04
Inferior wall	−14.7 ± 5.4	−20.3 ± 5.3	.0001
Septal wall	−20.7 ± 6.3	−26.3 ± 6.6	.0001
Papillary muscle level
Anteroseptal wall	−24 ± 3.1	−25.7 ± 5.9	.09
Anterior wall	−20.3 ± 5.9	−19.5 ± 6.9	.56
Lateral wall	−16.5 ± 6.7	−16.1 ± 6	.77
Posterior wall	−14.9 ± 7.3	−17.2 ± 6.3	.11
Inferior wall	−14.9 ± 6.7	−18.2 ± 5.7	.01
Septal wall	−20.3 ± 6.3	−25 ± 6	.001
Apical level
Anteroseptal wall	−22.1 ± 8.8	−27.4 ± 8.6	.005
Anterior wall	−20.1 ± 8.9	−26.2 ± 7.6	.0007
Lateral wall	−18.8 ± 8.8	−25.3 ± 5.9	.0001
Posterior wall	−19.7 ± 6.4	−23.8 ± 6.1	.03
Inferior wall	−21.7 ± 5.5	−24 ± 6.6	.07
Septal wall	−23.6 ± 8.1	−25.8 ± 9.9	.25

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