Remote Ischemic Conditioning in Pediatric Cancer Patients Receiving Anthracycline Chemotherapy: A Sham-Controlled Single-Blind Randomized Trial.

Background: Anthracycline cardiotoxicity is a concern in survivors of childhood cancers. Recent evidence suggests that remote ischemic conditioning (RIC) may offer myocardial protection. Objectives: This randomized sham-controlled single-blind study tested the hypothesis that RIC may reduce myocardial injury in pediatric cancer patients receiving anthracycline chemotherapy. Methods: We performed a phase 2 sham-controlled single-blind randomized controlled trial to determine the impact of RIC on myocardial injury in pediatric cancer patients receiving anthracycline-based chemotherapy. Patients were randomized to receive RIC (3 cycles of 5-minute inflation of a blood pressure cuff placed over 1 limb to 15 mm Hg above systolic pressure) or sham intervention. The intervention was applied within 60 minutes before initiation of the first dose and before up to 4 cycles of anthracycline therapy. The primary outcome was the plasma high-sensitivity cardiac troponin T (hs-cTnT) level. The secondary outcome measures included echocardiographic indexes of left ventricular systolic and diastolic function and the occurrence of cardiovascular events. Results: A total of 68 children 10.9 ± 3.9 years of age were randomized to receive RIC (n = 34) or sham (n = 34) intervention. Plasma levels of hs-cTnT showed a progressive increase across time points in the RIC (P < 0.001) and sham (P < 0.001) groups. At each of the time points, there were no significant differences in hs-cTnT levels or LV tissue Doppler and strain parameters between the 2 groups (all P > 0.05). None of the patients developed heart failure or cardiac arrhythmias. Conclusions: RIC did not exhibit cardioprotective effects in childhood cancer patients receiving anthracycline-based chemotherapy. (Remote Ischaemic Preconditioning in Childhood Cancer [RIPC]; NCT03166813).

Myocardial Deformation Imaging by Speckle-Tracking Echocardiography for Assessment of Cardiotoxicity in Children during and after Chemotherapy: A Systematic Review and Meta-Analysis.

BACKGROUND: Children with cancer and childhood cancer survivors (CCS) are at risk for developing chemotherapy-induced cardiomyopathy. Myocardial deformation imaging has shown potential in the early detection of subclinical myocardial damage with implications on therapeutic interventions and improvement of outcomes. The aim of this study was to perform a systemic review and meta-analysis of literature on the assessment of left ventricular and right ventricular myocardial deformation by speckle-tracking echocardiography at rest and during stress in children with cancer during and in survivors after chemotherapy. METHODS: A systematic review was performed through searching MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature, the Cochrane Central Register of Controlled Trials, and Scopus. Search hedges were created to cover the concepts of childhood cancer, chemotherapy, radiotherapy, anthracycline, cardiotoxicity, speckle-tracking, myocardial strain, and myocardial deformation. Two independent investigators reviewed the eligibility of articles for inclusion. The weighted mean difference in ventricular strain between pre- and postchemotherapy treatment and that between long-term CCS and healthy subjects were estimated using random-effect models with 95% CIs. Heterogeneity and publication bias were assessed using I2 statistics and the Egger test, respectively. RESULTS: Of the total of 8,703 records initially identified, 42 studies with a total of 5,430 children with cancer were included. Of these 42 studies that showed heterogeneities, nine assessed early myocardial injury during chemotherapy, 30 assessed late myocardial injury after chemotherapy with no publication bias, and three studied myocardial mechanics during stress. The main findings were as follows: (1) left ventricular systolic deformation is impaired in children with cancer during the initial treatment phase and among long-term CCS, while data on changes in right ventricular deformation are limited and inconclusive; (2) the predictive value of early reduction of myocardial strain imaging in forecasting subsequent development of cardiotoxicity is unknown, as it has not been studied; (3) limited data suggest the possibility of impaired left ventricular contractile mechanics during stress in CCS; and (4) cumulative anthracycline dose and chest-directed radiotherapy are consistently identified as factors associated with impaired myocardial deformation. CONCLUSIONS: Myocardial strain imaging by speckle-tracking echocardiography unveils early evidence of myocardial injury in children with cancer and long-term CCS. To support its adoption for clinical use, more data are required for the better understating of myocardial deformation parameters in the risk stratification of children with cancer and prediction of development of cardiomyopathy among CCS.

Three Decades of Follow-up After Surgical Closure of Subarterial Ventricular Septal Defect.

We determined the occurrence of aortic regurgitation (AR), AR progression and risk factors in patients followed up for up to three decades after closure of subarterial VSD. We reviewed the outcomes of 86 patients categorized into three groups: group I comprised 37 patients without AR and had VSD closure alone, group II comprised 40 patients with AR and had VSD closure without aortic valvoplasty, and group III comprised 9 patients with AR and required both VSD closure and aortic valvoplasty. Patients were followed up for 18.9 ± 7.3 years (median 19.5 years, range 3.5-36.6). At latest follow up, 54.7% (47/86) of patients had AR. The prevalence of progression of AR from any one grade to the next one higher was 37.2% (32/86). Freedom from AR progression was 75.6%, 52.1%, and 22.2% at 20 years of follow-up for groups I, II and III, respectively (p < 0.05). On the other hand, progression to moderate to severe AR occurred only in 4.7% (4/86). Group I and II patients were free from progression to significant AR, while only 33.3% of group III patients were free from progression on follow-up (p < 0.001). Multivariate Cox regression analysis showed that severity of preoperative AR was the significant risk factor for persistence and progression of postoperative AR after VSD closure. In conclusion, aortic regurgitation is common and may progress even after surgical repair of subarterial VSD. Severity of preoperative AR is the most significant predictor of persistence and progression of AR after surgical closure of subarterial VSD.

Two- and three-dimensional myocardial strain imaging in the interrogation of sex differences in cardiac mechanics of long-term survivors of childhood cancers.

We aimed to interrogate sex differences in cardiac mechanics using two-(2D) and three-(3D) dimensional speckle tracking echocardiography (STE) in survivors of childhood cancers. 83 survivors (43 males) aged 25.6 ± 6.1 years at 16.0 ± 6.1 years after anthracycline therapy and 42 healthy controls (21 males) were studied. 2D STE was performed to assess LV linear deformation in three principal directions, while 3D STE was performed to assess LV ejection fraction, global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), and global area strain (GAS). Receiver operating characteristic (ROC) curves were generated to to determine the usefulness of 2D and 3D echocardiographic indices to discriminate between survivors and controls. Survivors of both sex had significantly lower 2D and 3D strain indices compared with sex-specific controls (all p < 0.05). Among survivors, 2D GLS and GRS and all of the 3D indices were similar between males and females (all p > 0.05). Among cancer survivors, multivariate analysis revealed age at study (ß = - 0.26, p = 0.022) as a significant determinant of 3D GLS. The area under the ROC curve for 3D GLS was the largest at 0.89 amongst all 3D and 2D strain parameters, while that of 2D GLS was 0.83. For 3D GLS, a cut-off of 16.4% had a sensitivity of 85.7% and a specificity of 80.7% of differentiating survivors from controls. Notwithstanding the finding of impaired LV myocardial mechanics, the present study did not reveal evidence of sexual dimorphism in cardiac mechanics in long term survivors of childhood cancers.