Pulmonary hypertension is prevalent in adult patients with sickle cell disease, and is strongly associated with markers of hemolysis, in particular serum lactate dehydrogenase (LDH), and early mortality. Intravascular hemolysis leads to a state of resistance to nitric oxide (NO), mediated by NO scavenging by plasma oxyhemoglobin and by arginine degradation by plasma arginase. We hypothesized that serum LDH may represent a convenient biomarker of intravascular hemolysis and NO bioavailability, characterizing a clinical subphenotype of hemolysis-associated vasculopathy. In a cohort of 213 patients with sickle cell disease, we found statistically significant associations of LDH with low levels of hemoglobin and haptoglobin and high levels of reticulocytes, bilirubin, plasma hemoglobin, aspartate aminotransferase, arginase and soluble adhesion molecules. LDH isoenzyme fractionation confirmed predominance of LD1 and LD2, the principal isoforms within erythrocytes. In a subgroup, LDH levels closely correlated with plasma cell free hemoglobin, accelerated nitric oxide consumption by plasma and impaired vasodilatory responses to an NO donor. Remarkably, this simple biomarker was statistically associated with a clinical subphenotype of pulmonary hypertension, leg ulceration, priapism, and risk of death in patients with sickle cell disease. We propose that LDH elevation identifies patients with a syndrome of hemolysis-associated NO-resistance, endothelial dysfunction and end-organ vasculopathy. Figure Figure Figure Figure

Background. Pulmonary hypertension, defined by an elevated pulmonary artery systolic pressure measured by Doppler-echocardiogram, has been identified as the major predictor of death in the adult sickle cell disease population. While diastolic dysfunction is also observed in this population, the prevalence in unselected patients, the association with high pulmonary artery systolic pressure, and the attributable mortality remain unknown. Methods. Diastolic function parameters, pulmonary artery systolic pressures and right and left ventricular size and function were measured prospectively in 215 subjects with sickle cell disease. Associations between these parameters, lab and echocardiographic variables and prospective mortality were determined. Results. Diastolic dysfunction, measured by conventional and tissue-Doppler echocardiography, was present in 19% of patients with sickle cell disease. Diastolic dysfunction and pulmonary hypertension were both present in approximately 11% of patients and diastolic dysfunction accounted for approximately 10–20% of the variability in tricuspid regurgitant jet velocity. Importantly, Cox Proportional Hazards analysis revealed that diastolic dysfunction, as reflected by low E/A ratio, was associated with prospective mortality with a risk ratio of 1.9 (95%CI 1.0 to 3.7; p=0.028), even after adjustment for tricuspid regurgitant jet velocity. While pulmonary hypertension remained the dominant determinant of mortality risk, even after adjustment for measures of diastolic function (adjusted rate ratio of 5.3; 95% CI= 1.9 to15.0; p<0.001), the risk was additive such that patients with both risk factors had an odds ratio for death of 10.1 (95% CI= 3.2 to 31.9; p<0.001). Conclusions. Diastolic dysfunction and pulmonary hypertension due to other causes each contribute independently to prospective mortality in patients with sickle cell disease. Patients with both risk factors have an extremely poor prognosis. These data support the implementation of Doppler-echocardiographic screening of adult patients with sickle cell disease to identify individuals at high risk of death for intensified therapy. Figure Figure

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