Nonmyeloablative Hematopoietic Stem Cell Transplantation Improves a Marker of Diastolic Dysfunction in Patients with Sickle Cell Disease

Introduction: SCD is associated with significant morbidity and early mortality. Cardiopulmonary complications are increasingly being recognized as a common cause of death in adult patients with SCD. Further, both systolic dysfunction and an E/A ratio <1 (which suggests diastolic dysfunction) have been associated with premature mortality. HSCT is currently the only curative option available for patients with SCD. In this work, we sought to determine whether transthoracic echocardiographic (ECHO) parameters of either systolic or diastolic dysfunction improve after HSCT.

Methods: Patients with SCD who underwent nonmyeloablative HLA-matched sibling or haploidentical HSCT between September 2004 and July 2013 were included in this analysis. Patients undergoing HLA-matched sibling HSCT were conditioned with 300cGy total body irradiation (TBI) and alemtuzumab. Patients that received haploidentical HSCT were conditioned with 400cGy TBI and alemtuzumab. They further received post-transplant cyclophosphamide doses ranging from 0 to 100mg/kg. Laboratory and ECHO parameters performed at baseline were compared to those performed at one year post-HSCT. Normal E/A ratio was defined as >1, left atrial volume index (LAVI) as <29mL/m2 and ejection fraction as >55%.

Results: 42 patients who had ECHOs performed within the specified time frame were analyzed: 30 underwent HLA-matched sibling HSCT and 12 received haploidentical HSCT. Mean + standard deviation patient age at the time of HSCT was 32+10 years. 25 (60%) were male. The transplant was successful in 33 of the 42 (79%) patients. Hemoglobin increased from 8.8+1.8 at baseline to 11.4+2.1mg/dL at 1 year post-HSCT (p<0.0001). Mean baseline E/A ratio was 1.7+0.8 and EF was 63.2+5.9. E/A ratio decreased significantly to 1.5+0.4 (p=0.01) and EF decreased significantly to 59.8+6.3 (p=0.0007). The LAVI decreased significantly from 42.9+13.1 to 35.3+10.8 (p=0.0003) before and after transplant, respectively. There was a significant correlation between LAVI and hemoglobin (R=-0.58, p=0.0002 at baseline and R= -0.36, p=0.03 at 1 year). There was no significant correlation between E/A ratio or EF and hemoglobin (p>0.05). When controlling for the increase in hemoglobin, there was no significant decrease in LAVI.

When only evaluating the 6 patients with an E/A ratio <1, all successfully transplanted, mean age was 41.2+14.9 years, and all except 1 were male. Hemoglobin increased from 8.3+1.2 at baseline to 10.7+1.7mg/dL at 1 year post HSCT, though the change was not statistically significant in this small sample size (p=0.08). E/A ratio increased significantly from 0.79+0.12 at baseline to 1.13+0.38 at 1 year post HSCT (p=0.03). While 3 patients had an EF <55%, there were no patients transplanted with an EF <50%; therefore improvement in EF could not be assessed in patients with significant systolic dysfunction.

Conclusions: In patients with normal diastolic and systolic function, small changes in EF and E/A ratio were seen; however, the values remained within the normal range. LAVI improved, but unlike E/A ratio and EF, there was a significant correlation with hemoglobin level. Patients with diastolic dysfunction had an increase in E/A ratio to within the normal range. Our results demonstrate an improvement in one marker of early mortality in patients with SCD. A larger study is indicated to determine whether a low E/A ratio should be considered as an indication for nonmyeloablative HSCT in patients with SCD.