Circulating high-sensitivity troponin T and microRNAs as markers of myocardial damage during childhood leukaemia treatment.

BACKGROUND: We investigated whether plasma high-sensitivity cardiac troponin T (hs-cTnT) and circulating heart-associated microRNA (miRs) are increased in children with leukaemias during anthracycline-based chemotherapeutic treatment. METHODS: In vitro human pluripotent stem cell (hPSC)-derived cardiomyocyte model showed that miR-1, miR-133a, miR-208a, miR-208b, and miR-499 are released from cells into culture medium in a time- and dose-dependent manner on doxorubicin exposure. Left ventricular (LV) myocardial deformation and circulating heart-associated miRs and plasma hs-cTnT during and after completion of chemotherapy were determined in 40 children with newly diagnosed acute leukaemia. RESULTS: Significant reduction of LV global longitudinal strain and strain rates were found within 1 week after completion of anthracycline therapy in the induction phase of treatment (all p < 0.05). Hs-cTnT level peaked and miR-1 increased significantly at this time point. Log-transformed hs-cTnT correlated negatively with LV global systolic longitudinal strain (r = -0.38, p < 0.001). Receiver operating characteristic analysis revealed that area under the curve for changes in plasma hs-cTnT from baseline and plasma miR-1 levels in detecting a reduction in ≥20% of global longitudinal strain were respectively 0.62 (95% CI 0.38-0.87) and 0.62 (95% CI 0.40-0.84). CONCLUSION: Plasma hs-cTnT and circulating miR-1 may be useful markers of myocardial damage during chemotherapy in children with leukaemias. IMPACT: Heart-associated miRNAs including miR-1, miR-133a, miR-208a, miR-208b,and miR-499 were increased in the culture medium upon exposure of hPSC-derived cardiomyocytes to doxorubicin. Only miR-1 increased significantly during anthracycline-based therapy in paediatric leukaemic patients. In paediatric leukaemic patients, plasma hs-cTnT and circulating level of miR-1 showed the most significant increase within 1 week after completion of anthracycline therapy in the induction treatment phase. The study provides the first evidence of progressive increase in circulating miR-1 and plasma hs-cTnT levels during the course of anthracycline-based therapy in children with leukaemias, with hs-cTnT level also associated with changes in LV myocardial deformation.

Left Atrial Mechanics and Integrated Calibrated Backscatter in Anthracycline-Treated Long-Term Survivors of Childhood Cancers.

We tested the hypothesis that left atrial (LA) mechanics and myocardial calibrated integrated backscatter (cIB) are altered in anthracycline-treated long-term survivors of childhood cancers. Forty-nine survivors and 25 controls were studied. Survivors had significantly smaller maximal (p = 0.009) and minimal (p = 0.017) LA volumes and lower peak negative LA strains (p = 0.011). For left ventricular (LV) indices, survivors had significantly lower shortening fraction (p < 0.001), ejection fraction (p < 0.001) and mitral annular late diastolic velocity (p = 0.003). Myocardial cIB of the LA posterior wall, ventricular septum and LV posterior wall was significantly greater in survivors than controls (all p values <0.05). Peak negative LA strain was related to late diastolic mitral annular velocity (r = 0.27, p = 0.018), whereas LA cIB was related to the average of septal and LV posterior wall cIB (r = 0.54, p < 0.001). In conclusion, LA remodeling as characterized by contractile dysfunction and increased cIB suggestive of fibrosis occurs in adult survivors of childhood cancers.

Right Atrial Mechanics Long-Term after Biventricular Repair of Pulmonary Atresia or Stenosis with Intact Ventricular Septum.

BACKGROUND: This study tested the hypothesis that right atrial (RA) mechanics are altered in patients after repair of pulmonary atresia with intact ventricular septum (PAIVS) and pulmonary stenosis (PS) and to explore their relationships with right ventricular (RV) diastolic function and P-wave indices. METHODS: Thirty-six adult patients, 16 with PAIVS and 20 with PS patients, and 20 age-matched healthy subjects were studied. Right atrial mechanics were assessed using speckle tracking echocardiography (STE) with quantification of positive, negative, and total strain, and strain rates at ventricular systole (aSRs ), early diastole (aSRed ), and atrial contraction (aSRac ). Right ventricular diastolic function was assessed by Doppler interrogation and STE. Maximum P-wave duration and P-wave dispersion were measured. RESULTS: Compared with controls, PAIVS and PS patients had significantly lower RA positive and total strain, aSRs and aSRed (all P < 0.05). Parameters of RV diastolic function including transtricuspid early (E) and late (A) diastolic inflow velocities, E/A ratio, early diastolic tricuspid annular velocity (e), early to late diastolic annular velocity ratio, E/e ratio, and RV early diastolic strain rate were found to correlate significantly with RA positive and total strain and aSRed (all P < 0.05). Maximum P-wave duration and P-wave dispersion increased progressively across control, PS, and PAIVS groups (P for trend <0.001). Both P-wave indices correlated negatively with RA positive strain, total strain, and aSRed (all P < 0.05). CONCLUSION: Impairment of RA mechanics occurs in patients long term after repair of PAIVS and PS and is associated with RV diastolic dysfunction, longer P-wave duration, and greater P-wave dispersion.

Left ventricular mechanics in repaired tetralogy of Fallot with and without pulmonary valve replacement: analysis by three-dimensional speckle tracking echocardiography.

BACKGROUND: Altered septal curvature and left ventricular (LV) geometry secondary to right ventricular (RV) dilation render two-dimensional assessment of LV mechanics difficult in repaired tetralogy of Fallot (TOF) patients. The novel three-dimensional (3D) speckle tracking echocardiography enables comprehensive evaluation of true 3D LV mechanics. METHODS AND RESULTS: Seventy-six patients aged 23.6 ± 8.3 years, 55 with isolated repair (group I) and 21 with subsequent pulmonary valve replacement (group II), and 34 healthy controls were studied. Three-dimensional volume datasets were acquired for assessment of LV global and regional 3D strain, systolic dyssynchrony index (SDI), twist, twist gradient (twist/LV length), and ejection fraction. A global performance index was calculated as (global 3D strain•twist gradient)/SDI. The septal curvature and LV eccentricity were determined from the mid-ventricular short-axis. Compared with controls, group I and II patients had significantly reduced LV global 3D strain, LV twist, twist gradient, septal curvature, and global performance index, and greater LV systolic and diastolic eccentricity and SDI (all p<0.05). All but the four apical LV segments in patients had reduced regional 3D strain compared with controls (all p<0.05). Septal curvature correlated with LV global 3D strain (r=0.41, p<0.001), average septal strain (r=0.38, p<0.001), twist (r=0.32, p<0.001), twist gradient (r=0.33, p<0.001), and global performance index (r=0.43, p<0.001). CONCLUSIONS: Adverse 3D LV mechanics as characterized by impaired global and regional 3D systolic strain, mechanical dyssynchrony, and reduced twist is related to reduced septal curvature in repaired TOF patients with and without pulmonary valve replacement.