The findings from this large prospective, multicenter study of patients with sickle cell anemia demonstrate an independent association between high hemolytic rate and an increased estimated pulmonary artery systolic pressure as assessed by Doppler echocardiography. The findings additionally demonstrate an independent association between worse anemia and LV lateral E/e′ ratio. Furthermore, in this study elevations of both TRV and LV lateral E/e′ ratio were associated with functional impairment as assessed by the six-minute walk test. The mean six-minute walk distance among the hemoglobin SS patients with TRV ≥3.0 m/sec in this study was similar to the distance reported in patients with chronic thromboembolic pulmonary hypertension.32
While we have not analyzed mortality in Walk-PHaSST, these findings relating exercise capacity to estimated pulmonary artery systolic pressure and LV lateral E/e′ ratio in this large cohort parallel our previous observations with regard to mortality from the NIH.2, 3
They also provide support in adults for our recent findings in children that echocardiographic estimates of elevated right ventricular systolic pressure and LVDD may be associated with reduced exercise capacity.18
Thus, our present findings are supportive of echocardiographic screening for PH and LVDD in SCD, and suggest that these observations may have functional relevance in terms of assessing exercise capacity.
Increased TRV as estimated by Doppler echocardiography is a useful screening test for suspected PH including patients with SCD6, 7, 23
and is a marker of increased mortality in adults with SCD.2–5
In confirmed PH (diagnosed by RHC), approximately one-half of the cases were attributable to increased pulmonary vascular resistance meeting criteria for pulmonary arterial hypertension with the majority of the remainder having pulmonary venous hypertension attributed to LVDD.23
This large international study confirms independent associations of increased TRV with hemolytic severity, elevated LV filling pressure, renal dysfunction, and high circulating erythropoietin concentrations in SCD patients. The independent association of increased BUN with an increased TRV is consistent with our previous report of an association of renal disease with elevated TRV.3
The independent association of increased erythropoietin with increased TRV is also consistent with some previous observations33–35
but in contrast to others.36, 37
Circulating erythropoietin concentrations reflect the degree of tissue hypoxia,38
and the association of a greater level of erythropoietin with a higher TRV may serve as a marker of the degree of tissue hypoxia, which appears to be associated with the development of PH in other conditions.39
Additionally, erythropoietin has functions other than the stimulation of erythropoiesis, such as regulation of the development of endothelial progenitor cells and angiogenesis;40, 41
the inducement of such processes could contribute to vascular remodeling and the risk of developing PH. The circulating erythropoietin concentrations could also be a marker for potential contributions of increased erythropoiesis to increased pulmonary artery pressure. Developing erythroblasts release placental growth factor into the circulation. Placental growth factor up-regulates the production of inflammatory mediators and the potent vasoconstrictor, endothelin-1. Studies in animals and humans suggest a potential causative role for placental growth factor in PH.42
LVDD as assessed by Doppler echocardiography is also a marker of increased mortality in adults with SCD2
. The results of the present study confirm that echocardiographic markers of LVDD are prevalent in sickle cell anemia and point to independent associations of older age, worse anemia, higher systolic blood pressure and elevated BMI with an elevated LV lateral E/e′ ratio. The degree of anemia, rather than the rate of hemolysis, appeared to be the stronger independent predictor of LVDD as assessed by the LV lateral E/e′ ratio in the present study. This observation is in contrast to elevated TRV, for which the strongest independent predictor was the rate of hemolysis rather than the degree of anemia. Anemia and elevated BMI have been reported as risk factors for LVDD in other settings as well.43, 44
There are a number of limitations to this study. 1) Doppler estimation of LV filling pressure is challenging in the setting of preserved LV systolic function.24, 45, 46
SCD patients have chronic anemia, high cardiac output, and volume overload, which may affect the interpretation of non-invasive measures. Doppler parameters of LV diastolic function have not been reported in SCD patients undergoing invasive measurement of LV filling pressure. 2) The study did not include the measurement of inflammatory markers, such as high-sensitivity C-reactive protein. Sickle cell disease is associated with chronic inflammation, which itself has been implicated in the cardiopulmonary complications of this disorder.47
3) Reference ranges for markers of hemolysis including lactate dehydrogenase varied considerably among the sites participating in this study. The use of principal component analysis for developing a hemolytic component that reflects shared variability among several markers of hemolysis has the advantage of permitting adjustment for each participating center in developing the hemolytic component. 4) Our findings do not fully explain PH, LVDD and limited six-minute walk distance in sickle cell anemia. The multivariate models presented in , and could explain 25%, 14% and 34% respectively of these measurements. Further research is needed to more fully understand these complications.
Moving forward, clinical trials may be warranted to evaluate strategies to prevent or delay the development of PH and LVDD in sickle cell anemia, but there are challenges in targeting hemolysis and the degree of anemia. The interventions assessing a Gardos channel inhibitor as well as the phosphodiesterase type 5 inhibitor sildenafil were both associated with increased vaso-occlusive complications.48, 49
Hydroxyurea administration, which reduces hemolysis, raises hemoglobin concentration and increases hemoglobin F percentage, has not been associated with a lower TRV in a number of large cross-sectional studies.3, 16
Prospective studies are needed to evaluate whether hydroxyurea is effective in reducing the development of PH and/or LVDD. Blood transfusions could also be expected to improve left-sided cardiac function and the six-minute walk distance in hemoglobin SS patients. Chronic transfusion therapy may therefore be an ideal approach to prevent and treat both abnormalities, but would be complicated by iron overload and alloimmunization. We suggest that hydroxyurea, blood transfusion, and novel approaches be investigated in patients at increased risk of developing PH and/or elevated LV lateral E/e′ ratio, as these complications independently predict poor outcome in patients with sickle cell anemia.