Echocardiographic markers of elevated pulmonary pressure and left ventricular diastolic dysfunction are associated with exercise intolerance in adults and adolescents with homozygous sickle cell anemia in the United States and United Kingdom

Abstract

Background: Noninvasively assessed pulmonary pressure elevations and left ventricular (LV) diastolic dysfunction are associated with increased mortality in adults with sickle cell disease, but their relationship to exercise intolerance has not been evaluated prospectively.

Methods and results: Echocardiography, 6-minute walk distance, hemolytic rate, and serum concentrations of ferritin and erythropoietin were evaluated in a cohort of 483 subjects with homozygous hemoglobin S in the U.S. and U.K. Walk-Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk-PHaSST) study. Tricuspid regurgitation velocity, which reflects systolic pulmonary artery pressure, was 2.7 to <3.0 m/s (mean±SD, 2.8±0.1) in 26% of the subjects and ≥3.0 m/s (mean±SD, 3.4±0.4) in 11%. The LV lateral E/e' ratio, which has been shown to reflect LV filling pressure in other conditions but has not been studied in sickle cell disease, was significantly higher in the groups with tricuspid regurgitation velocity ≥2.7 m/s. Increased hemolysis (P<0.0001), LV lateral E/e' ratio (P=0.0001), blood urea nitrogen (P=0.0002), and erythropoietin (P=0.002) were independently associated with an increased tricuspid regurgitation velocity. Furthermore, female sex (P<0.0001), older age (P<0.0001), LV lateral E/e' ratio (P=0.014), and tricuspid regurgitation velocity (P=0.019) were independent predictors of a shorter 6-minute walk distance.

Conclusions: Echocardiography-estimated elevated pulmonary artery systolic pressure and LV lateral E/e' ratio were independently associated with poor exercise capacity in a large cohort of patients with sickle cell anemia. Controlled trials investigating whether strategies to prevent or delay pulmonary hypertension and/or LV diastolic dysfunction will improve exercise capacity and long-term outcomes in sickle cell anemia should be considered. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00492531.

Conflict of interest statement

Disclosures

Roberto F. Machado, Kathryn L. Hassell, Jane A. Little, Dean E. Schraufnagel, Claudia R. Morris, Oswaldo L. Castro, Vandana Sachdev, and Jonathan C. Goldsmith report no relevant conflict of interest related to the subject of this manuscript.

Figures

Figure 1

Linear relationship of TRV with a. hemolytic component and b. LV lateral E/e′ ratio in participants with hemoglobin SS at steady state.

Figure 1

Linear relationship of TRV with a. hemolytic component and b. LV lateral E/e′ ratio in participants with hemoglobin SS at steady state.

Figure 2

Linear relationship of LV lateral E/e′ ratio with hemoglobin concentration in participants with hemoglobin SS.

Figure 3

a. Mean (SD) six-minute walk distance according to TRV groups in participants with hemoglobin SS. P for trend of change in distance across the three groups is <0.0001. b. Linear relationship between six-minute walk distance and LV lateral wall E/e′ ratio in the same population.

Figure 3

a. Mean (SD) six-minute walk distance according to TRV groups in participants with hemoglobin SS. P for trend of change in distance across the three groups is <0.0001. b. Linear relationship between six-minute walk distance and LV lateral wall E/e′ ratio in the same population.