Risk Factors for Echocardiography-Determined Cardiopulmonary Abnormalities In Sickle Cell Anemia In the Walk-PHaSST Study

Elevated right ventricular pressure [1] and left ventricular diastolic dysfunction [2] as assessed by echocardiography are each independently associated with increased mortality in adults with sickle cell anemia. To determine independent risk factors for these echocardiographic findings, we examined a large, prospective, multi-center international cohort in a cross-sectional manner. In a previous study of adults with sickle cell disease, we identified histories of cardiac and renal disease, higher values for serum lactate dehydrogenase (LDH), alkaline phosphatase, and systolic blood pressure, and lower values for transferrin to have independent associations with elevated right ventricular systolic pressure as estimated by echocardiography [1].

Walk-PHaSST (treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy) includes an on-going observational study of sickle cell disease patients at nine United States Centers and one United Kingdom Center. In the screening phase of the study, clinical evaluation and echocardiography were performed on 720 subjects. For this analysis, we determined among 483 patients with hemoglobin SS baseline clinical associations with the echocardiographic measurements of tricuspid regurgitation velocity (TRV), which reflects right ventricular systolic pressure, and left ventricular lateral wall E/Ea ratio, which reflects left ventricular filling pressure as a measure of diastolic dysfunction. The study prospectively defined moderately elevated TRV as 2.7–2.9 m/sec and markedly elevated TRV as ≥3.0 m/sec. A hemolytic component was derived by principal component analysis from four markers of hemolysis: reticulocyte percent, serum LDH, aspartate aminotransferase and bilirubin.

Of 483 hemoglobin SS patients, the median age was 35 years (range of 12 to 69 years) and the gender distribution was 250 females and 233 males. TRV was measured in 453 patients, lateral wall E/Ea was measured in 436 and hemolytic component was calculated in 406. TRV was 2.7–2.9 m/sec in 22% and ≥3.0 m/sec in 17%.

By ordinal logistic regression, an increase of age of 10 years was independently associated with a 1.5-fold increase in the odds of progressively higher TRV categories (95% CI of 1.2–1.8; P <0.0005), an increase in the hemolytic component of 2 SD with a 2.4-fold increase in the odds of progressively higher categories (95% CI of 1.5–3.8; P <0.0005), a log increase in the lateral wall E/Ea ratio with a 3.2-fold increase in the odds (95% CI of 1.6–6.6; P=0.001), and a serum creatinine >1.4 mg/dL with a 2.1-fold increase in the odds (95% CI of 1.0–4.3; P=0.047).

By linear regression, older age was independently associated with a higher log lateral wall E/Ea ratio (beta=0.005; P <0.0005) as were serum creatinine >1.4 mg/dL (beta=0.23; P <0.0005) and lower hemoglobin concentration (beta=-0.002; P=0.022).

The findings of this large prospective, multicenter, international study of patients with sickle cell anemia emphasizes the association of older age, severe hemolytic anemia, renal dysfunction, and left ventricular diastolic dysfunction with high TRV, a previously confirmed marker of early mortality. Clinical trials are indicated to test whether strategies to correct hemolytic anemia and to prevent renal dysfunction in adults and adolescents with sickle cell anemia may prevent or delay the development of left ventricular diastolic dysfunction and/or pulmonary hypertension.

References:

1. Gladwin, M.T., et al., Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med, 2004. 350(9): p.886-95.

2. Sachdev, V., et al., Diastolic dysfunction is an independent risk factor for death in patients with sickle cell disease. J Am Coll Cardiol, 2007. 49(4): p.472-9.

No relevant conflicts of interest to declare.