Assessment of anthracycline-induced cardiotoxicity in childhood cancer survivors during long-term follow-up using strain analysis and intraventricular pressure gradient measurements.

BACKGROUND: Cardiac dysfunction due to cardiotoxicity from anthracycline chemotherapy is a leading cause of morbidity and mortality in childhood cancer survivors (CCS), and the cumulative incidence of cardiac events has continued to increase. This study identifies an adequate indicator of cardiac dysfunction during long-term follow-up. PROCEDURE: In total, 116 patients (median age: 15.5 [range: 4.7-40.2] years) with childhood cancer who were treated with anthracycline were divided into three age groups for analysis (C1: 4-12 years of age, C2: 13-18 years of age, C3: 19-40 years of age), and 116 control patients of similar ages were divided into three corresponding groups (N1, N2, and N3). Layer-specific strains were assessed for longitudinal strain (LS) and circumferential strain (CS). The total and segmental intraventricular pressure gradients (IVPG) were also calculated based on Doppler imaging of the mitral inflow using Euler's equation. RESULTS: Conventional echocardiographic parameters were not significantly different between the patients and controls. All layers of the LS and inner and middle layers of the basal and papillary CS in all ages and all IVPGs in C2 and C3 decreased compared to those of corresponding age groups. Interestingly, basal CS and basal IVPG in CCS showed moderate correlation and both tended to rapidly decrease with aging. Furthermore, basal IVPG and anthracycline dose showed significant correlations. CONCLUSIONS: Basal CS and total and basal IVPGs may be particularly useful indicators of cardiotoxicity in long-term follow-up.

Comparing a knowledge-based 3D reconstruction algorithm to TomTec 3D echocardiogram algorithm in measuring left cardiac chamber volumes in the pediatric population.

BACKGROUND: Three-dimensional echocardiography (3DE) is an emerging method for volumetric cardiac measurements; however, few vendor-neutral analysis packages exist. Ventripoint Medical System Plus (VMS3.0+) proprietary software utilizes a validated Magnetic resonance imaging (MRI) database of normal ventricular and atrial morphologies to calculate chamber volumes. This study aimed to compare left ventricular (LV) and atrial (LA) volumes obtained using VMS3.0+ to Tomtec echocardiography analysis software. METHODS: Healthy controls (n = 98) aged 0-18 years were prospectively recruited and 3D DICOM datasets focused on the LV and LA acquired. LV and LA volumes and ejection fractions were measured using TomTec Image Arena 3D LV analysis package and using VMS3.0+. Pearson correlation coefficients, Bland-Altman's plots, and intraclass coefficients (ICC) were calculated, along with analysis time. RESULTS: There was a very good correlation between Ventripoint Medical System (VMS) and Tomtec LV systolic (r2  = .88, ICC .89 [95% CI .81, .94]), and diastolic (r2  = .88, ICC .90 [95% CI .77, .95]) volumes, and between VMS and Tomtec LA diastolic (r2  = .75, ICC .89 [95% CI .81, .93]) and systolic (r2  = .88, ICC .91 [95% CI .78, .96]) volumes on linear regression models. Natural log transformations eliminated heteroscedasticity, and power transformations provided the best fit. The time (mins) to analyze volumes using VMS were less than using Tomtec (LV VMS 2.3 ± .5, Tomtec 3.3 ± .8, p < .001; LA: VMS 1.9 ± .4, Tomtec 3.4 ± 1.0, p < .001). CONCLUSIONS: There was a very good correlation between knowledge-based (VMS3.0+) and 3D (Tomtec) algorithms when measuring 3D echocardiography-derived LA and LV volumes in pediatric patients. VMS was slightly faster than Tomtec in analyzing volumetric measurements.

Deep insight into cardiac dysfunction in children and young adults with Wolff-Parkinson-White syndrome using speckle tracking imaging.

Although ventricular pre-excitation via accessory pathways (APs) causes cardiac dysfunction in children and young adults with Wolff-Parkinson-White (WPW) syndrome, the underlying cardiac dysfunction mechanisms are unclear. This study aimed to characterize cardiac dysfunction and clarify sensitive cardiac dysfunction indicators in WPW syndrome patients classified by the APs location with a layer-specific strain analysis. Twenty-four patients with WPW syndrome with a mean age of 14.1 years (6.9-21.6 years) (11 cases: type A with a left-sided AP [WA group], 13 cases: type B with a right-sided AP [WB group]), and 37 age-matched normal controls (N group) were examined. We measured the left ventricle (LV), base-, mid-, and apical-level of circumferential strain (CS), and longitudinal strain (LS) using a layer-specific strain with speckle tracking imaging. Dyssynchrony was also measured based on the timing of the radial strain at each segment. Peak endomyocardial base- and mid-level of CS was lower in both the WA and WB groups compared to the N group. Peak mid-myocardial and epimyocardial base-level of CS and peak mid-myocardial mid-level of CS were lower only in the WB group compared to the N group. Peak LS in all three layers was lower only in the WB group compared to the N group. There was a significant difference between the patient and normal groups for the dyssynchrony index only at the base-level, and there was no significant difference between the groups for LV ejection fraction (EF). Layer-specific strain decreased in more sites in the WB group despite the normal EF value. Layer-specific strains are sensitive indicators for the detection of the early stages of cardiac dysfunction.

A multicenter study of three-dimensional echocardiographic evaluation of normal pediatric left ventricular volumes and function.

BACKGROUND: Three-dimensional echocardiography (3DE) evaluation of left ventricular (LV) volume and function in pediatrics compares favorably with cardiac magnetic resonance imaging. The aim of this study was to establish from a multicenter, normal pediatric z-score values of 3DE left ventricular volumes and function. METHODS: Six hundred and ninety-eight healthy children (ages 0-18 years) were recruited from five centers. LV 3DE was acquired from the 4-chamber view. A vendor-independent software analyzed end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), and ejection fraction (EF) using semi-automated quantification. Body surface area (BSA)-based z-scores were generated. Intraobserver and interobserver variability were calculated using intraclass correlation (ICC) and repeatability coefficient (RC). RESULTS: Z-scores were generated for ESV, EDV, and SV. The ICC for intraobserver variability for EDV, ESV, and SV was 0.99, 0.99, and 0.99, respectively. The ICC for interobserver variability for EDV, ESV, and SV was 0.98, 0.94, and 0.98, respectively. The RC for intraobserver and interobserver variability for LV EF was 4.39% (95% CI: 3.01, 5.59) and interobserver was 7.08% (95%CI: 5.51, 8.42). CONCLUSIONS: We report pediatric z-scores for normal LV volumes using the semi-automated method from five centers, enhancing its generalizability. 3DE evaluation of LV volumes and EF in pediatric patients is highly reproducible.

Exercise echocardiography demonstrates potential myocardial damage in patients with repaired tetralogy of Fallot using layer-specific strain analysis.

INTRODUCTION: Exercise stress echocardiography and layer-specific strains are emerging as important tools for cardiac assessment. This study was aimed to evaluate layer-specific strains and torsion parameters during exercise in order to investigate the characteristics of cardiac dysfunction in patients with repaired tetralogy of Fallot and to detect subclinical left ventricular dysfunction. MATERIALS AND METHODS: Thirteen patients with repaired tetralogy of Fallot (median age, 17.3 [interquartile range, 14.5-22.9] years; 6 males) and 13 controls (median age, 28.5 [interquartile range, 27.6-31.6] years; 13 males) underwent echocardiography at rest and during supine exercise. Layer-specific longitudinal strain and circumferential strain of three myocardial layers (endocardium, midmyocardium, and epicardium), torsion, and untwisting rate were measured using two-dimensional speckle-tracking echocardiography. RESULTS: Peak endocardial papillary circumferential strain (-21.1 ± 2.6% vs. -25.8 ± 3.8%, p = 0.007), midmyocardial apical circumferential strain (-11.1 ± 4.0% vs. -15.6 ± 3.2%, p = 0.001), epicardial apical circumferential strain (-11.1 ± 4.0% vs. -15.6 ± 3.2%, p = 0.021), and torsion (8.9 ± 6.0 vs. 14.9 ± 4.8 degree, p = 0.021) were significantly lower in the repaired tetralogy of Fallot group than in the control group during exercise, though no significant difference was found between patients and controls at rest. CONCLUSIONS: Analysis of layer-specific strains and torsion parameters during exercise could detect subclinical left ventricular dysfunction in patients with repaired tetralogy of Fallot, which might reflect potential myocardial damage, at a stage where these parameters have normal values at rest. This finding provides new insight into the mechanisms of cardiac dysfunction in patients with repaired tetralogy of Fallot.

Development of suction force during early diastole from the left atrium to the left ventricle in infants, children, and adolescents.

Although the suction force that moves blood into the left ventricle during early diastole is thought to play an important role in diastolic function, there have been a few studies of this phenomenon in normal children. Suction force is measured as the intraventricular pressure difference (IVPD) and intraventricular pressure gradient (IVPG), which is calculated as IVPD divided by left ventricular length. The purpose of this study was to determine the suction force in infants, children, and adolescents using IVPD and IVPG. We included 120 normal children categorized into five groups based on age: G1 (0-2 years), G2 (3-5 years), G3 (6-8 years), G4 (9-11 years), and G5 (12-16 years). The total, basal, and mid-apical IVPD and IVPG were calculated using color M-mode Doppler imaging of the mitral valve inflow using the Euler equation. The total IVPD increased with age from G1 to G5 (1.75 + 0.51 vs. 2.95 + 0.72 mmHg, respectively; p < 0.001), due to an increase in mid-apical IVPD with constant basal IVPD. Although total IVPG was constant, mid-apical IVPG was larger in G5 than in G1 (0.21 + 0.06 vs. 0.16 + 0.07 mmHg/cm, respectively; p = 0.006). Total, basal, and mid-apical IVPDs were significantly correlated with age and the parameters of heart size and mitral annular e'. Mid-apical IVPG correlated with age and e' positively, but basal IVPG did with age negatively and did not with e'. The suction force increased at the mid-apical segment, correlating with increasing heart size and developing left ventricular relaxation, even after adjustment for left ventricular length.

New insight into the intraventricular pressure gradient as a sensitive indicator of diastolic cardiac dysfunction in patients with childhood cancer after anthracycline therapy.

Cardiac dysfunction due to cardiotoxicity from anthracycline chemotherapy is a leading cause of morbidity and mortality in survivors of childhood cancer. The intraventricular pressure gradient (IVPG) of the left ventricle (LV) is the suction force of blood from the left atrium to the LV apex during early diastole and is a sensitive indicator of diastolic function. We assessed IVPG as a new indicator of the cardiac dysfunction in survivors of childhood cancer after anthracycline therapy. We performed a prospective echocardiographic study on 40 survivors of childhood cancer aged 6-26 years who received anthracycline therapy (group A) and 53 similar-age normal controls (group N). The subjects were divided into the younger groups, N1 and A1 (age < 16 years); older groups, N2 and A2 (age ≥ 16 years). IVPG was calculated using color M-mode Doppler imaging of the mitral inflow using Euler's equation. Total IVPG was divided into the basal and mid-to-apical IVPG to demonstrate more clearly the mechanisms of the LV diastolic suction force. The total anthracycline dose was 16.2-600.0 mg/m2 (median 143.5 mg/m2). Total IVPG significantly decreased in group A2 compared with that in group N2 (0.39 ± 0.07 vs. 0.29 ± 0.11 mmHg/cm; p = 0.010). The mid-to-apical IVPG significantly decreased in groups A1 and A2 compared with that in groups N1 and N2, respectively (N1 vs. A1: 0.20 ± 0.05 vs. 0.16 ± 0.05 mmHg/cm, p = 0.036; N2 vs. A2: 0.21 ± 0.06 vs. 0.14 ± 0.06 mmHg/cm, p = 0.001). Basal IVPG, E wave, and E/e' were not significantly different between patients and normal controls. The total and mid-to-apical IVPG, especially mid-to-apical IVPG, could be sensitive new indicators in survivors of childhood cancer after anthracycline therapy.

In-Depth Insight Into the Mechanisms of Cardiac Dysfunction in Patients With Childhood Cancer After Anthracycline Treatment Using Layer-Specific Strain Analysis.

BACKGROUND: Anthracycline cardiotoxicity affects clinical outcomes, and its early detection using methods that rely on conventional echocardiography, such as left ventricular ejection fraction (LVEF) is difficult. This study aimed to evaluate the characteristics and the differences in cardiac dysfunction among childhood cancer survivors in 3 age groups using layer-specific strain analysis in a wide age range.Methods and Results:The 56 patients (median age: 15 [range: 6.8-40.2] years) who had been treated with anthracycline for childhood cancer were divided into 3 age groups (C1: 6-12 years, C2: 13-19 years, C3: 20-40 years) after anthracycline treatment, and 72 controls of similar ages were divided into 3 corresponding groups (N1, N2, and N3). Layer-specific longitudinal strain (LS) and circumferential strain (CS) of 3 myocardial layers (endocardium, midmyocardium, and epicardium) were determined using echocardiography. Myocardial damage had not occurred yet in C1. Endocardial CS at the basal level was less in C2 than in N2. Endocardial CS at all levels and midmyocardial CS at the basal and papillary levels were lower in C3 than in N3. LVEF and LS were not significantly different between patients and controls. CONCLUSIONS: Among survivors of childhood cancer, impaired myocardial deformation starts in adolescence and extends from the endocardium towards the epicardium and from the base towards the apex with age. These findings are a novel insight into the time course of anthracycline cardiotoxicity.

Assessment of early diastolic intraventricular pressure gradient in the left ventricle among patients with repaired tetralogy of Fallot.

Assessment of left ventricular (LV) dysfunction is vital in patients with repaired tetralogy of Fallot (rTOF). The early diastolic intraventricular pressure gradient (IVPG) in the LV plays an important role in diastolic function. IVPG is calculated as the intraventricular pressure difference divided by the LV length, which allows to account for differences in LV size and therefore calculate IVPG in children. We aimed to investigate the mechanisms of LV diastolic dysfunction by measuring mid-to-apical IVPG as an indicator of the active suction force sucking blood from the left atrium into the LV. We included 38 rTOF patients and 101 healthy controls. The study population was stratified based on age group into children (4-9 years), adolescents (10-15 years), and adults (16-40 years). IVPGs were calculated based on mitral inflow measurements obtained using color M-mode Doppler echocardiography. Although total IVPGs did not differ between rTOF patients and controls, mid-to-apical IVPGs in adolescents and adults were smaller among rTOF patients than among controls (0.15 ± 0.05 vs. 0.21 ± 0.06 mmHg/cm, p < 0.05; 0.09 ± 0.07 vs. 0.17 ± 0.05 mmHg/cm, p < 0.001; respectively). Additionally, only mid-to-apical IVPG correlated linearly with peak circumferential strain (ρ = 0.217, p = 0.011), longitudinal strain (ρ = -0.231, p = 0.006), torsion (ρ = -0.200, p = 0.018), and untwisting rate in early diastole (ρ = -0.233, p = 0.006). In rTOF, the mechanisms underlying diastolic dysfunction involve reduced active suction force, which correlates with reduced LV deformation in all directions.

Novel Findings of Early Cardiac Dysfunction in Patients With Childhood-Onset Inflammatory Bowel Disease Using Layer-Specific Strain Analysis.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at a higher risk of developing cardiovascular diseases than healthy individuals, owing to persistent chronic inflammation and treatment effects. This study aimed to assess left ventricular function in patients with childhood-onset IBD using layer-specific strain analysis and to identify early indicators of cardiac dysfunction in them. METHODS: A total of 47 patients with childhood-onset ulcerative colitis (UC), 20 patients with Crohn's disease (CD), and 75 age- and sex-matched healthy control subjects were included in this study. Conventional echocardiographic measurements of layer-specific (ie, endocardium, midmyocardium, and epicardium) global longitudinal strain and global circumferential strain (GCS) were evaluated in these participants. RESULTS: Layer-specific strain analysis showed that global longitudinal strain was lower in all layers for the UC (P < .001) and CD (P < .001) groups, regardless of the age at onset, but that GCS was only lower in the midmyocardial (P = .032) and epicardial (P = .018) layers in the CD group than in the control group. Although the mean left ventricular wall thickness was not significantly different among the groups, it was significantly correlated with the GCS of the endocardial layer in the CD group (ρ= -0.615; P = .004), suggesting that thickening of the left ventricular wall occurred as a compensatory mechanism to maintain the endocardial strain in the CD group layer. CONCLUSIONS: Children and young adults with childhood-onset IBD displayed decreased midmyocardial deformation. Layer-specific strain could also be useful to identify indicators of cardiac dysfunction in patients with IBD.

Patients with inflammatory bowel disease are at a higher risk of developing cardiovascular disease than healthy individuals. Our study revealed that children and young adults with childhood-onset inflammatory bowel disease already have reduced myocardial deformability.

Tricuspid Valve Tethering Is Associated with Residual Regurgitation after Valve Repair in Hypoplastic Left Heart Syndrome: A Three-Dimensional Echocardiographic Study.

BACKGROUND: Tricuspid valve regurgitation (TR) is a risk factor for morbidity and mortality in children with hypoplastic left heart syndrome (HLHS). Surgical tricuspid valve (TV) repair is common, but durable repair remains challenging. The aim of this study was to examine mechanisms of TR requiring surgery, features associated with unsuccessful repair, and TV changes after surgical repair. METHODS: Thirty-six patients with HLHS requiring TV repair (TVR) and 36 matched control subjects with HLHS were assessed using two-dimensional and three-dimensional echocardiography. Using three-dimensional echocardiography, TV coordinates from the annulus, leaflet, and ventricle were used to measure annular, leaflet, prolapse, and tethering values and anterior papillary muscle angle. TR grade and ventricular size, function, and shape were assessed using two-dimensional echocardiography. RESULTS: Patients requiring TVR had greater total leaflet prolapse, larger TV annular and leaflet areas, and flatter annuli, with no difference in tethering, coaptation index, or anterior papillary muscle angle. In patients with HLHS, successful TVR at follow-up (58%) was associated with preoperative total leaflet prolapse (especially posterior). Unsuccessful repair was associated with preoperative tethering of the septal leaflet. TVR in patients with HLHS caused a reduction of total annular and leaflet size and reduced prolapse and tethering of the posterior leaflet but did not affect anterior leaflet prolapse or septal leaflet tethering. CONCLUSIONS: Features associated with TVR include a flattened and dilated TV annulus with leaflet prolapse. The additional presence of a tethered septal leaflet before TVR is associated with significant postoperative TR. Current surgical techniques, predominantly posterior annuloplasty and commissuroplasty, adequately address annular size and posterior leaflet pathology, but not septal leaflet tethering. Individualized and innovative surgical techniques are vital to improve surgical repair success.