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.

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.

Right Ventricular Electromechanical Dyssynchrony and Its Relation to Right Ventricular Remodeling, Dysfunction, and Exercise Capacity in Ebstein Anomaly.

BACKGROUND: Abnormal atrioventricular and intraventricular electrical conduction and dysfunction of the functional right ventricle (fRV) are common in Ebstein anomaly (EA). However, fRV mechanical dyssynchrony and its relation to fRV function are poorly characterized. We evaluated fRV mechanical dyssynchrony in EA patients in relation to fRV remodeling, dysfunction, and exercise intolerance. METHODS: We retrospectively analyzed data from nonoperated EA patients and age-matched controls who underwent echocardiography, cardiovascular magnetic resonance imaging, and cardiopulmonary exercise testing to quantify right ventricular (RV) remodeling, dysfunction, and exercise capacity. The relation of these to fRV dyssynchrony was retrospectively investigated. Right ventricular mechanical dyssynchrony was defined by early fRV septal activation (right-sided septal flash), RV lateral wall prestretch/late contraction, postsystolic shortening, and intra-RV delay using two-dimensional strain echocardiography. The SD of time to peak shortening among the fRV segments was calculated as a parameter of mechanical dispersion. RESULTS: Thirty-five EA patients (10 of whom were <18 years of age) and 35 age-matched controls were studied. Ebstein anomaly patients had worse RV function and increased intra-RV dyssynchrony versus controls. Nineteen of 35 (54%) EA patients had early septal activation with simultaneous stretch and consequent late activation and postsystolic shortening of RV lateral segments. Intra-fRV mechanical delay correlated with fRV end-diastolic volume index (r = 0.43, P < .05) and fRV end-systolic volume index (r = 0.63, P < .001). The fRV ejection fraction was lower in EA with versus without right-sided septal flash (44.9 ± 11.0 vs 54.2 ± 8.2, P = .012). The fRV mechanical dispersion correlated with the percentage of predicted peak VO2 (r = -0.35, P < .05). CONCLUSIONS: In EA, fRV mechanical dyssynchrony is associated with fRV remodeling, dysfunction, and impaired exercise capacity. Mechanical dyssynchrony as a therapeutic target in selected EA patients warrants further study.

Clinical outcomes of simultaneous phototherapeutic keratectomy and photoastigmatic keratectomy.

This study was aimed to assess the outcomes of simultaneous phototherapeutic keratectomy (PTK) and photoastigmatic keratectomy (PAK), with special attention to astigmatic correction. We comprised 70 eyes of 70 patients who underwent simultaneous PTK and PAK in patients having granular corneal dystrophy and band keratopathy with refractive astigmatism of 1 diopter (D) or more. Preoperatively and 6 months postoperatively, we assessed corrected uncorrected distance visual acuity (UDVA), distance visual acuity (CDVA), manifest spherical equivalent, refractive astigmatism, corneal astigmatism, and higher-order aberrations (HOAs). LogMAR CDVA significantly improved, from 0.27 ± 0.27 preoperatively, to 0.13 ± 0.21 postoperatively (Paired t test, p < 0.001). LogMAR UDVA also significantly improved, from 0.70 ± 0.32 preoperatively, to 0.57 ± 0.41 postoperatively (p = 0.043). Refractive astigmatism significantly decreased, from 2.12 ± 0.95 D preoperatively, to 0.89 ± 0.81 D postoperatively (p < 0.001). Corneal astigmatism also significantly decreased, from 2.17 ± 0.90 D preoperatively, to 1.08 ± 0.71 D postoperatively (p < 0.001). Corneal HOAs did not significantly change, from 0.54 ± 0.30 µm preoperatively, to 0.48 ± 0.20 µm postoperatively (p = 0.140). No significant complications occurred in any eye. Simultaneous PTK and PAK treatment is effective not only for improving visual acuity, but also for reducing astigmatism.

Impaired right and left ventricular function and relaxation induced by pulmonary regurgitation are not reversed by tardive antifibrosis treatment.

Pulmonary regurgitation (PR) after repair of tetralogy of Fallot (rTOF) is associated with progressive right (RV) and left (LV) ventricular dysfunction and fibrosis. However, angiotensin II receptor blockade therapy has shown mixed and often disappointing results. The aim of this study was to serially assess changes in biventricular remodeling, dysfunction, and interactions in a rat model of isolated severe PR and to study the effects of angiotensin II receptor blockade. PR was induced in Sprague-Dawley rats by leaflet laceration. Shams (n = 6) were compared with PR (n = 5) and PR + losartan treatment (n = 6). In the treatment group, oral losartan (50 mg·kg-1·day-1) was started 6 wk after PR induction and continued for 6 wk until the terminal experiment. In all groups, serial echocardiography was performed every 2 wk until the terminal experiment where biventricular myocardium was harvested and analyzed for fibrosis. PR and PR + losartan rats experienced early progressive RV dilatation by 2 wk which then stabilized. RV systolic dysfunction occurred from 4 wk after insult and gradually progressed. In PR rats, RV dilatation caused diastolic LV compression and impaired relaxation. PR rats developed increased RV fibrosis compared with shams. Although losartan decreased RV fibrosis, RV dilatation and dysfunction were not improved. This suggests that RV dilatation is an early consequence of PR and affects LV relaxation. RV dysfunction may progress independent of further remodeling. Reduced RV fibrosis was not associated with improved RV function and may not be a viable therapeutic target in rTOF with predominant RV volume loading.NEW & NOTEWORTHY The time-course of RV dilatation and the mechanisms of biventricular dysfunction caused by PR have not been well characterized and the effect of losartan in volume-overloaded RV remains controversial. Our findings suggest that severe PR induces early onset of RV dilatation and dysfunction with little progression after the first 4 wk. The RV dilatation distorts LV geometry with associated impaired LV relaxation. Losartan reduced RV fibrosis but did not reverse RV dilatation and dysfunction.

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.

Changes in left ventricular blood flow during diastole due to differences in chamber size in healthy dogs.

Vorticity is a novel index that reflects diastolic function of left ventricle. The size of the ventricle can influence the ventricular diastolic blood flow. We evaluated effect of ventricular size on diastolic function and diastolic intracardiac blood flow using a particular species of dogs, which has a wide range of body size. Vector flow mapping was used for evaluation of intracardiac blood flow, and intraventricular pressure gradient (IVPG) was used for evaluation of diastolic function. 58 dogs weighing 1.3-42.3 kg were included in this study. Vorticity was found to be inversely proportional to the length of the ventricular chamber. Intraventricular pressure difference was positively correlated with the length of the left ventricle, whereas IVPG was not. This study showed that the vorticity is influenced by the size of the left ventricle independently of other factors. To evaluate the hemodynamic state of each individual appropriately by using vorticity and IVPD, ventricular size should be taken into account especially in the field of veterinary medicine and human pediatric and adolescent cardiology.

In-Depth Insight Into the Mechanisms of Cardiac Dysfunction in Patients With Type 1 Diabetes Mellitus Using Layer-Specific Strain Analysis.

BACKGROUND: Although the subclinical left ventricular (LV) dysfunction caused by diabetes mellitus (DM) results in a high risk of death and heart failure, the details of cardiac dysfunction across a wide age range remain unclear. The aim of this study was to assess LV dysfunction in patients with type 1 DM (T1DM) using layer-specific strain analysis by echocardiography.Methods and Results:The 52 patients (median age: 23 [range: 5-40] years) with T1DM were divided into 3 age groups (D1: 5-14 years, D2: 15-24 years, D3: 25-40 years); 78 age- and sex-similar controls were divided into 3 corresponding groups (C1, C2, and C3). Layer-specific longitudinal strain (LS) and circumferential strain (CS) of the 3 myocardial layers (endocardium, midmyocardium, and epicardium) were determined using echocardiography. Strains did not decrease in D1. Epicardial and midmyocardial CS at the basal level and LS in all layers were decreased in D2 compared with C2. CS at the basal level and LS in all layers were lower in D3 than in C3. The strains correlated with the duration of T1DM and LV wall thickness. CONCLUSIONS: In patients with T1DM, longitudinal deformation in all layers and epicardial and midmyocardial circumferential deformation at the basal level decreased from the late teens, which correlated with the duration of the disease and LV hypertrophy.

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.

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.

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.

Mechanisms of Left Ventricular Dysfunction Assessed by Layer-Specific Strain Analysis in Patients With Repaired Tetralogy of Fallot.

BACKGROUND: Left ventricular (LV) dysfunction in patients with repaired tetralogy of Fallot (rTOF) is an important risk factor for adverse outcomes. The aim of this study was to assess the details and time course of such LV dysfunction using layer-specific strain analysis by echocardiography.Methods and Results:The 66 patients with rTOF (mean age, 16.3±9.3 years) were divided into 3 groups (T1: 4-10 years, T2: 11-20 years, T3: 21-43 years), and 113 controls of similar age (mean age, 17.2±9.3 years) were divided into 3 corresponding groups (C1, C2, and C3). Layer-specific longitudinal strain (LS) and circumferential strain (CS) of 3 myocardial layers (endocardial, midmyocardial, and epicardial) were determined by echocardiography. Basal and papillary endocardial CS values were decreased in T1 compared with C1. With the exception of papillary epicardial CS, basal/papillary CS and LS of all 3 layers decreased in T2 compared with C2. Excepting papillary epicardial CS, all other values were decreased in T3 compared with C3. CONCLUSIONS: Potential myocardial damage was found in the endocardium at the basal and papillary levels of the LV in young patients with rTOF, extending from the endocardium to the epicardium and from the base to the apex. This is the possible time course of LV dysfunction in patients with rTOF.