Survivors of Pediatric Hematopoietic Stem Cell Transplant Exhibit Progressive Diastolic Dysfunction Over Years of Follow-up.

BACKGROUND: Patients who have undergone hematopoietic stem cell transplant (HSCT) during childhood carry a higher risk of diastolic heart failure (HF). The rate of progression of diastolic dysfunction in aging pediatric patients is unknown, and more difficult to assess in young patients secondary to changes in diastolic indices as they grow.

OBJECTIVE: HSCT patients at our center were previously found to have decline in diastolic function indices 1 year after HSCT. This study provides follow-up of this cohort and uses age-normalized Z-scores to assess whether declining diastolic function noted at 1-year post-HSCT persists, worsens, or improves over time.

STUDY DESIGN: Children < 21 yrs who underwent HSCT at Boston Children's/Dana-Farber from 2005-2008 with ≥ 3 surveillance echoes, including one pre-HSCT, were included. Diastolic measures included mitral inflow (E/A ratio) and Doppler tissue imaging of left ventricular lateral wall (LV lateral e'), LV septal wall (septal e') and RV free wall (RV e'). Systolic function was measured by LV ejection fraction (LVEF). Z-scores were used to normalize by age, and > ±2 SD were defined as abnormal in linear modeling of diastolic dysfunction and systolic dysfunction over time. In a subset of patients with adequate post-HSCT images of the entire left atrium (LA), LA volume and LA strain analysis was also performed.

RESULTS: 61 patients were included (41% F, median age at HSCT 10.7 yr, median follow-up time 7.4 yr). Diastolic indices Z-scores declined by -0.045/yr (LV lateral e'), -0.06/yr (LV septal e'), and -0.14/yr (RV e'), (p < 0.01). E/A ratio Z-score increased by 0.034/yr (p = 0.028). Linear modeling demonstrated that LV lateral e' and LV septal e' would become abnormal at 25 and 20 years, respectively, post-HSCT, whereas RV e' would become abnormal sooner, at 12.6 years. LVEF Z-score declined by -0.04/yr (p < 0.01) and was estimated to become abnormal at 40 years post-HSCT. Exposure to total body radiation (TBI) was associated with worsening diastolic indices, lower LVEF (p ≤ 0.002), and decreased LA reservoir strain (42.0 % vs 45.0 %, p=0.016), and conduit strain (-31.5% vs -35.1%, p=0.029), although there was significant overlap between TBI and anthracycline exposure. Treatment with anthracyclines even at low doses (median 150mg/m2 ) was associated with declining LVEF, but not with change in diastolic indices.

CONCLUSIONS: Long-term survivors of childhood HSCT exhibit decline in both LV and RV diastolic function indices. These results inform the rate of progression of LV and RV diastolic dysfunction indices over time in long-term survivors of pediatric HSCT. A significant association was observed between TBI and diastolic dysfunction and decline in LVEF. Treatment with anthracyclines even at low doses was associated with mild decline in LVEF. Results can inform a lifespan perspective on disease management in this population, encourage clinicians and patients to be vigilant in following guideline-directed surveillance echocardiography, and inform anticipatory responses by clinicians as patients transition from pediatric to adult care.