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1.  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 US and UK 
Circulation  2011;124(13):1452-1460.
Non-invasively assessed pulmonary pressure elevations and left ventricular diastolic dysfunction (LVDD) are associated with increased mortality in adults with sickle cell disease (SCD), but their relationship to exercise intolerance has not been evaluated prospectively.
Methods and Results
Echocardiography, six-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 US and UK Walk-PHaSST study. Tricuspid regurgitation velocity (TRV), which reflects systolic pulmonary artery pressure, was 2.7 to <3.0 m/sec (mean±SD 2.8±0.1) in 26% of the subjects and ≥3.0 m/sec (3.4±0.4) in 11%. LV lateral E/e′ ratio, which has been shown to reflect LV filling pressure in other conditions but has not been studied in SCD, was significantly higher in the groups with TRV ≥2.7 m/sec. Increased hemolysis (P<0.0001), LV lateral E/e′ ratio (P=0.0001), BUN (P=0.0002) and erythropoietin (P=0.002) were independently associated with an increased TRV. Further, female gender (P<0.0001), older age (P<0.0001), LV lateral E/e′ ratio (P=0.014), and TRV (P=0.019) were independent predictors of a shorter six-minute walk distance.
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 LVDD will improve exercise capacity and long-term outcomes in sickle cell anemia should be considered.
PMCID: PMC3183314  PMID: 21900080
sickle cell anemia; pulmonary hypertension; left ventricular diastolic dysfunction; echocardiography; six-minute walk
2.  Prevalence and risk factors for pulmonary artery systolic hypertension among sickle cell disease patients in Nigeria 
American journal of hematology  2008;83(6):485-490.
Pulmonary artery systolic hypertension is common and associated with increased mortality among adult sickle cell disease (SCD) patients in the United States. While the prevalence of SCD is highest in sub-Saharan Africa, the frequency of pulmonary artery systolic hypertension and the risk factors for the development of pulmonary hypertension have not been reported from Africa. We studied 208 hydroxyurea naïve Nigerian SCD patients at steady state and 94 healthy controls. Pulmonary artery systolic hypertension was defined prospectively as tricuspid regurgitant jet velocity ≥2.5 meters per second. Results were compared with a previously published US prospective SCD cohort. Only 7% of Nigerians compared to 46% of US adults with SCD were >35 years. Tricuspid regurgitant jet velocity was ≥2.5 m/second in 25% of Nigerian SCD patients. Higher jet velocity was associated with greater serum globulin (P=0.002), blood urea nitrogen (P=0.019) and lactate dehydrogenase concentrations (P=0.026) and with inability to walk >300 meters in six minutes (P=0.042). Compared to the US cohort, Nigerian patients had more hemolysis as indicated by lower hemoglobin and higher lactate dehydrogenase concentrations (P ≤0.003). Pulmonary hypertension is common among Nigerian SCD patients. The public health implication of this finding is significant considering the potential number of individuals at risk for this complication. Better understanding of the long term outcome of pulmonary hypertension and causes of death in SCD and the institution of preventive measures are major public health challenges for Africa. The inclusion of African sites in sickle cell pulmonary hypertension clinical trials should be encouraged.
PMCID: PMC3415268  PMID: 18306362
Pulmonary hypertension; sickle cell disease; Nigeria
3.  Improvement in hemolysis and pulmonary arterial systolic pressure in adult patients with sickle cell disease during treatment with hydroxyurea 
American journal of hematology  2009;84(8):530-532.
Elevated pulmonary arterial systolic pressure is strongly associated with mortality in patients with sickle cell disease (SCD). A tricuspid regurgitant velocity (TRV) of 2.5 m/s or greater by trans-thoracic echocardiogram is a key marker of risk [1–3]. The pathophysiologic mechanism involves release from the red cell during intravascular hemolysis of cell-free plasma hemoglobin and arginase [4]. Hydroxyurea is the only drug approved by the Food and Drug Administrations specifically for SCD. It acts by increasing levels of fetal hemoglobin, which inhibits sickling, and has been shown to reduce the incidence of vaso-occlusive crisis (VOC), and prolong survival in patients with sickle cell disease [5,6]. Because fetal hemoglobin also reduces the rate of hemolysis in SCD, hypothetically, hydroxyurea might also reduce the severity of hemolysis-linked vascular dysfunction and pulmonary hypertension. Herein, we describe five patients with sickle cell disease having elevated pulmonary arterial systolic pressure who exhibited improvement in their baseline laboratory parameters of hemolysis, accompanied by reduced TRV, during treatment with hydroxyurea. Hydroxyurea may have a role in the management of selected patients with elevated TRV.
PMCID: PMC2766189  PMID: 19536844
4.  Prospective Echocardiography Assessment of Pulmonary Hypertension And Its Potential Etiologies In Children With Sickle Cell Disease 
The American journal of cardiology  2009;104(5):713-720.
Pulmonary hypertension (PH) is associated with adverse outcomes in adults with sickle cell disease (SCD) but its importance in children is less clear. We define the incidence and etiologies of PH in pediatric patients with SCD. Children with SCD (n = 310) and matched controls (n = 54) were prospectively enrolled under basal conditions. Participants underwent echocardiography, pulse oximetry, 6-minute walk, and hematologic testing. Echocardiographic measures were compared between SCD and control subjects before and after adjusting for hemoglobin. Correlation of echocardiographic and clinical parameters was performed. Tricuspid regurgitation velocity (TRV) was elevated compared to controls (2.28 vs. 2.10 m/s, p <0.0001). Increased TRV was associated with left ventricular diastolic diameter, hemoglobin, and estimated left atrial pressure. TRV remained elevated when controlled for left ventricular diameter and left atrial pressure. An echocardiography-derived pulmonary resistance was not significantly different between SCD and control patients, although it was elevated in the SCD subgroup with elevated TRV. When controlled for hemoglobin, TRV was no longer statistically different, but pulmonary insufficiency velocity, septal wall thickness and estimated pulmonary resistance were statistically higher. TRV, pulmonary insufficiency end diastolic velocity, and markers of increased cardiac output correlated with indicators of adverse functional status including history of acute chest syndrome, stroke, transfusions, and 6-minute walk. In conclusion, children with SCD have mildly increased TRV that correlated with increased cardiac output and left ventricular filling pressures. Hemoglobin adjusted analysis also suggests contribution of primary vascular changes.
PMCID: PMC3197734  PMID: 19699350
Pulmonary hypertension; Tricuspid regurgitation; Pulmonary vascular resistance; Sickle cell
Pediatric hematology and oncology  2007;24(3):159-170.
Pulmonary arterial hypertension (PAH), once considered a rare complication of sickle cell disease (SCD) and thalassemia, appears to be more common in adults with hemoglobinopathy than previously appreciated. On prospective screening of adults with SCD, approximately one-third of adults are found on echocardiography to have a tricuspid regurgitant jet velocity (TRV) of 2.5 m/s or higher, many of whom are asymptomatic. Dyspnea on exertion is the most common presenting symptom. This TRV abnormality is a marker for approximately 40% 3-year mortality in adults, and it is associated with laboratory values suggestive of more severe intravascular hemolysis. Release of hemoglobin and arginase from lysed red cells causes scavenging of nitric oxide (NO) and catabolism of L-arginine, the obligate substrate for NO synthase. The resulting impairment in NO bioavailability is associated with pulmonary vasoconstriction, endothelial dysfunction, thrombosis, and eventual development of plexogenic arterial lesions, the histological hallmark of all forms of PAH. Undoubtedly, additional pathophysiological mechanisms will also play a role in its multifactorial pathogenesis. Early data from children with SCD indicate a similar prevalence of elevated TRV, but the prognostic implications of this remain to be established. Individual patient diagnosis of PAH requires confirmation by right heart catheterization studies and individualized management. Hemolysis-associated PAH with impairments in NO bioavailability is being identified in thalassemia and other hemolytic disorders, and may be a general consequence of long-standing, severe intravascular hemolytic anemia.
PMCID: PMC2065860  PMID: 17454785
sickle cell; thalassemia; pulmonary hypertension; nitric oxide; arginase
6.  Diastolic Dysfunction Is an Independent Risk Factor for Death in Patients With Sickle Cell Disease 
The goal of this study was to characterize left ventricular diastolic function in the sickle cell disease (SCD) population and to relate echocardiographic measures of dysfunction with pulmonary hypertension and mortality.
Pulmonary hypertension has been identified as a predictor of death in the adult SCD population. Although diastolic dysfunction is also observed in this population, its prevalence, association with high pulmonary artery systolic pressure, and attributable mortality remain unknown.
Diastolic function assessment using tissue Doppler imaging was performed in a group of 141 SCD patients. Conventional echocardiographic parameters of diastolic function were performed in a total of 235 SCD patients.
Diastolic dysfunction was present in 18% of patients. A combination of diastolic dysfunction and pulmonary hypertension was present in 11% of patients, and diastolic dysfunction accounted for only 10% to 20% of the variability in tricuspid regurgitation (TR) jet velocity. Diastolic dysfunction, as reflected by a low E/A ratio, was associated with mortality with a risk ratio of 3.5 (95% confidence interval 1.5 to 8.4, p < 0.001), even after adjustment for tricuspid regurgitation (TR) jet velocity. The presence of both diastolic dysfunction and pulmonary hypertension conferred a risk ratio for death of 12.0 (95% confidence interval 3.8 to 38.1, p < 0.001).
Diastolic dysfunction and pulmonary hypertension each contribute independently to prospective mortality in patients with SCD. Patients with both risk factors have an extremely poor prognosis. These data support the implementation of echocardiographic screening of adult patients with SCD to identify high-risk individuals for further evaluation.
PMCID: PMC2082057  PMID: 17258093
7.  Elevated Pulse Pressure is Associated with Hemolysis, Proteinuria and Chronic Kidney Disease in Sickle Cell Disease 
PLoS ONE  2014;9(12):e114309.
A seeming paradox of sickle cell disease is that patients do not suffer from a high prevalence of systemic hypertension in spite of endothelial dysfunction, chronic inflammation and vasculopathy. However, some patients do develop systolic hypertension and increased pulse pressure, an increasingly recognized major cardiovascular risk factor in other populations. Hence, we hypothesized that pulse pressure, unlike other blood pressure parameters, is independently associated with markers of hemolytic anemia and cardiovascular risk in sickle cell disease. We analyzed the correlates of pulse pressure in patients (n  =  661) enrolled in a multicenter international sickle cell trial. Markers of hemolysis were analyzed as independent variables and as a previously validated hemolytic index that includes multiple variables. We found that pulse pressure, not systolic, diastolic or mean arterial pressure, independently correlated with high reticulocyte count (beta  =  2.37, p  =  0.02) and high hemolytic index (beta  =  1.53, p = 0.002) in patients with homozygous sickle cell disease in two multiple linear regression models which include the markers of hemolysis as independent variables or the hemolytic index, respectively. Pulse pressure was also independently associated with elevated serum creatinine (beta  =  3.21, p  =  0.02), and with proteinuria (beta  =  2.52, p  =  0.04). These results from the largest sickle cell disease cohort to date since the Cooperative Study of Sickle Cell Disease show that pulse pressure is independently associated with hemolysis, proteinuria and chronic kidney disease. We propose that high pulse pressure may be a risk factor for clinical complications of vascular dysfunction in sickle cell disease. Longitudinal and mechanistic studies should be conducted to confirm these hypotheses.
PMCID: PMC4257593  PMID: 25478953
British journal of haematology  2010;150(1):102-107.
N-terminal (NT) pro-brain natriuretic peptide (proBNP) ≥160 ng/l has a 78% positive predictive value for pulmonary hypertension and is associated with increased mortality in US sickle cell disease patients, but the importance in sickle cell disease patients in Africa is not known. In a cross-sectional study at Ahmadu Bello University Teaching Hospital, Shika-Zaria, Nigeria, we studied 133 hydroxycarbamide-naïve Nigerian sickle cell anaemia patients aged 18-52 years at steady-state and 65 healthy controls. Twenty-six percent of patients versus 5% of controls had NT-proBNP ≥160 ng/l (P=0.0006). By logistic regression among the patients, human immunodeficiency virus seropositivity, higher serum ferritin and lower haemoglobin or higher lactate dehydrogenase independently predicted elevated NT-proBNP. After adjustment for haemoglobin concentration, elevated NT-proBNP concentration was associated with an estimated 7.8-fold increase in the odds of severe functional impairment, defined as an inability to walk more than 300 m in six min (95% confidence interval 1.5-32.6; P=0.005). Similarly, elevated tricuspid regurgitation velocity was associated with an estimated 5.6-fold increase in the odds of functional impairment (95% confidence interval 1.5-21.0; P=0.011). In conclusion, NT-proBNP elevation is common and is associated with markers of anaemia, inflammation and iron status and with severe functional impairment among sickle cell anaemia patients in Nigeria.
PMCID: PMC2907438  PMID: 20408845
sickle cell disease; N-terminal pro-brain natriuretic peptide; six-minute walk; haemolysis; Africa
9.  Relative Systemic Hypertension in Patients with Sickle Cell Disease is Associated with Risk of Pulmonary Hypertension and Renal Insufficiency 
American Journal of Hematology  2008;83(1):15-18.
We analyzed entry data from 163 adult hemoglobin SS and Sβ0 thalassemia patients enrolled in the prospective Sickle Cell Pulmonary Hypertension Screening Study and stratified their ECHO-determined tricuspid regurgitant jet velocity (TRV) and serum creatinine concentration according to three blood pressure categories. TRV was ≥2.5 m/sec in 27% of the patients with systolic blood pressure (SBP) <120 mm Hg and diastolic blood pressure (DBP) <70 mm Hg, in 37% with SBP 120–139 mm Hg or DBP 70–89 mm Hg, and in 93% with SBP 140 mm Hg or DBP 90 mm Hg or higher (P <0.0005 for trend). Serum creatinine concentration was 1.0 mg/dL or higher in 7% of patients with SBP <120 mm Hg and DBP <70 mm Hg, in 17% with SBP 120–139 mm Hg or DBP 70–89 mm Hg and 50% with SBP 140 mm Hg or DBP 90 mm Hg or higher (P <0.0005 for trend). Over two years of follow-up, there were trends for more frequent progression to elevated TRV (P = 0.073) or creatinine (P = 0.038) values according to the higher systemic blood pressure categories. Our findings suggest that systolic SBP 120–139 mm Hg or DBP 70–89 mm Hg defines a category of relative systemic hypertension in patients with sickle cell disease that is associated with increased risk for pulmonary hypertension and renal dysfunction. Whether antihypertensive and/or nitric oxide donor therapy in sickle cell disease patients with relative hypertension prevents these and other complications should be determined by clinical trials.
PMCID: PMC3398810  PMID: 17696198
10.  Prevalence of pulmonary hypertension in sickle cell anaemia patients of a tertiary hospital in Nigeria 
Sickle cell disease (SCD) is an inherited haemoglobinopathy characterised by recurrent organ hypoxia-reperfusion cycles which may result in repeated organ damage including the lungs and heart. In SCD, pulmonary hypertension is a known complication that may precede or complicate acute chest syndrome which is often fatal. This study seeks to know the prevalence of pulmonary hypertension and its relationship with clinical and laboratory parameters in sickle cell disease patients attending a tertiary hospital in Lagos.
Materials and Methods:
This was a case — control study involving patients with sickle cell disease recruited from adult sickle cell clinic of Lagos State University Teaching Hospital, Ikeja and HbAA controls matched for age and sex from a tertiary educational institution in Lagos. Both the patients and controls were subjected to echocardiography and pulmonary hypertension was deduced from their cardiac tricuspid regurgitant jet velocity. Other parameters measured were age, body mass index, full blood count, red cell indices, foetal haemoglobin, chest X-ray, liver function tests, lactate dehydrogenase and pulmonary function tests. Consenting patients were 56 HbSS in steady state and 28 HbAA controls matched for age and sex. Data was analysed using SPSS version 16.0.
The mean age of patients was 22 ± 6 years. In two 2 of 56 (3.6%) of the participants with sickle cell disease, the pulmonary artery pressure was > 25mmHg and there was significant difference in the mean of the pulmonary artery pressure of the control and that of the patients (P-value 0.013). Also, using the appropriate correlation tests, there was significant relationship between the pulmonary artery pressure and lactate dehydrogenase, aspartate transferase and haematocrit in patients with sickle cell disease.
Sickle cell disease is an independent cause of pulmonary artery hypertension. Variation in cardiovascular reactions to recurrent hyperhaemolysis and hyperdynamic state in sickle cell disease may explain differences in the development of cardiac complications. Exploration of these reactions may reveal other therapeutic measures to prevent complications in sickle cell disease. Clinical assessment of adult patients with sickle cell disease should include echocardiography.
PMCID: PMC4003721  PMID: 24791052
Lagos Nigeria; pulmonary hypertension; sickle cell disease
11.  Markers of severe vaso-occlusive painful episode frequency in children and adolescents with sickle cell anemia 
The Journal of Pediatrics  2011;160(2):286-290.
To identify factors associated with frequent severe vaso-occlusive pain crises in a contemporary pediatric cohort of sickle cell anemia (SCA)enrolled in a prospective study of pulmonary hypertension and the hypoxic response in sickle cell disease (SCD).
Study design
Clinical and laboratory characteristics of children with SCA who had ≥3 severe pain crises requiring health care in the preceding year were compared with subjects with <3 such episodes.
Seventy-five children (20%) reported ≥3 severe pain episodes in the preceding year, and 232 (61%) had none. Frequent pain episodes were associated with older age (OR 1.2; 95% CI 1.1–1.3; P<0.0001), α-thalassemia trait (OR 3.5; 1.6–6.7; P=0.002), higher median hemoglobin (OR 1.7; 95% CI: 1.2–2.4; P<0.003) and lower lactate dehydrogenase (LDH) concentration (OR 1.82; 95% CI: 1.07–3.11; P = 0.027). Children with high pain frequency also had an increased iron burden (serum ferritin 480 vs. 198 μg/L; P=0.006) and higher median tricuspid regurgitation jet velocity (2.41 vs. 2.31 m/s; P=0.001). Neither hydroxy urea use nor fetal hemoglobin levels were significantly different according to severe pain history.
In our cohort of children with SCA increasing age was associated with higher frequency of severe pain episodes as were α-thalassemia, iron overload, higher hemoglobin and lower LDH concentration and higher tricuspid regurgitation velocity.
PMCID: PMC3258348  PMID: 21890147
Sickle cell anemia; vaso-occlusive crisis; pain
British journal of haematology  2010;149(3):436-445.
Pulmonary hypertension (PH) in sickle cell disease (SCD) is an emerging and important clinical problem. In a single-institution adult cohort of 365 patients, we investigated lipid and lipoprotein levels and their relationship to markers of intravascular hemolysis, vascular dysfunction and PH. In agreement with prior studies, we confirm significantly decreased plasma levels of total cholesterol, high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) in SCD vs. ethnically-matched healthy controls. Several cholesterol parameters correlate significantly with markers of anemia, but not endothelial activation or PH. More importantly, serum triglyceride levels are significantly elevated in SCD compared to controls. Elevated triglyceride levels correlate significantly with markers of hemolysis (lactate dehydrogenase and arginase; both p<0.0005), endothelial activation (soluble E-selectin, p<0.0001; soluble P-selectin, p=0.02; soluble vascular cell adhesion molecule-1, p=0.01), inflammation (leukocyte count, p=0.0004; erythrocyte sedimentation rate, p=0.02) and PH (amino-terminal brain natriuretic peptide, p=0.002; prevalence of elevated tricuspid regurgitant velocity (TRV), p<0.001). In a multivariate analysis, triglyceride levels correlate independently with elevated TRV (p=0.002). Finally, forearm blood flow studies in adult patients with SCD demonstrate a significant association between increased triglyceride/HDL-C ratio and endothelial dysfunction (p<0.05). These results characterize elevated plasma triglyceride levels as a potential risk factor for PH in SCD.
PMCID: PMC3212812  PMID: 20230401
13.  Pattern of chronic lung lesions in adults with sickle cell disease in Lagos, Nigeria 
Background: The vascular response to recurrent tissue hypoxia and reperfusion following red blood cell sickling causes acute chest syndrome and chronic lung disease. The purpose of this study was to determine the pattern of chronic lung lesions and possible risk factors in sickle cell patients in lagos, Nigeria.
Methods: From July 2012 to April 2013, Pulmonary function test (PFT) and chest-x-ray were determined in 56 eligible patients with sickle cell disease. Full blood count, red cell indices, hemoglobin F level, oxygen saturation, liver function tests, lactate dehydrogenase and tricuspid regurgitant jet velocity were measured.
Results: The mean age of the patients was 22±6 years. The mean forced vital capacity was low (76.49%±16). Abnormal PFTs were restrictive lung lesion (53%), obstructive lesions (3.7%) and mixed lesions (11%). The vital capacity had negative correlation with the white cell count and platelet count while it had positive correlation with age. There were no significant differences when normal and abnormal PFTs were compared based on the following laboratory data: lactate dehydrogenase (244 vs. 301), hematocrit (22.7 vs. 23.6), fetal hemoglobin (6.2% vs. 4.2%), mean corpuscular hemoglobin concentration (33.7 vs 33.3), aspartate transferase (34.2 vs. 35.1), tricuspid regurgitant jet velocity (1.3 vs. 0.92) and oxygen saturation (95.8 vs. 95.5). Abnormal x-ray findings were present in 84% of participants. Chest x ray showed ischemic (17%), congestive (69%), fibrotic and inflammatory (14%) changes.
Conclusion: Chronic lung lesion is common in sickle cell disease associated with rising white cell count, platelet count. All adult patients should have regular spirometry done to ensure early detection.
PMCID: PMC3841774  PMID: 24294468
Sickle cell disease; Tricuspid; Regurgitant; Jet velocity; Spirometry.
The Journal of infectious diseases  2010;202(5):791-800.
Chronic intravascular hemolysis leads to nitric oxide (NO) depletion and pulmonary hypertension in sickle cell disease. To test whether this pathophysiology occurs in malaria, we examined 53 children admitted to hospital with severe malaria (excluding cerebral malaria) and 31 age-matched controls in Mali.
Severity of hemolysis was assessed from plasma free hemoglobin (Hb) and arginase-1 levels. NO metabolism was assessed by whole blood nitrite levels and plasma NO consumption. Effects on the cardiovascular system and endothelial function were assessed by using echocardiography to measure peak tricuspid regurgitant jet velocity (TRV) and from plasma levels of N-terminal prohormone brain natriuretic peptide (NT-proBNP) and soluble vascular cell adhesion molecule-1 (sVCAM-1).
Children with severe malaria had higher plasma Hb and arginase-1 levels, reduced whole blood nitrite levels and increased NO consumption relative to controls. They also had increased pulmonary arterial pressures (p < 0.05) with elevated levels of NT-proBNP and sVCAM-1 (p < 0.001).
Children with severe malaria have increased pulmonary pressures and myocardial wall stress. These complications are consistent with NO depletion from intravascular hemolysis, and indicate that the pathophysiologic cascade from intravascular hemolysis to NO depletion and its cardiopulmonary effects is activated in children with severe malaria.
PMCID: PMC3206728  PMID: 20662718
malaria; Plasmodium falciparum; nitric oxide (NO); intravascular hemolysis; whole blood nitrite; NO consumption; tricuspid regurgitation velocity (TRV); NT-proBNP; myocardial wall stress; sVCAM-1; endothelial dysfunction
15.  Dysregulated Arginine Metabolism, Hemolysis-Associated Pulmonary Hypertension and Mortality in Sickle Cell Disease 
Sickle cell disease is characterized by a state of nitric oxide (NO) resistance and limited bioavailability of L-arginine, the substrate for NO synthesis. We hypothesized that increased arginase activity and dysregulated arginine metabolism contribute to endothelial dysfunction, pulmonary hypertension and patient outcome.
To explore the role of arginase in sickle cell disease pathogenesis, pulmonary hypertension and prospective mortality.
Plasma amino acid levels, plasma and erythrocyte arginase activities, and pulmonary hypertension status as measured by Doppler-echocardiogram were prospectively obtained in outpatients with sickle cell disease. Patients were followed for survival up to 49 months.
Urban, tertiary care center and community clinics.
Two hundred twenty-eight patients with sickle cell disease aged 18 to 74 years and 36 control subjects.
Main Outcome Measures
Plasma amino acid levels, plasma and erythrocyte arginase activities, diagnosis of pulmonary hypertension, and mortality.
Plasma arginase activity was significantly elevated in patients with sickle cell disease, with highest activity found in subjects with secondary pulmonary hypertension. Arginase activity correlated with the arginine-to-ornithine ratio, and lower ratios were associated with greater severity of pulmonary hypertension and with mortality in this population (risk ratio: 2.5; 95% confidence interval [1.2, 5.2], p=0.006). Global arginine bioavailability, characterized by the arginine-to-(ornithine plus citrulline) ratio, was also strongly associated with mortality (risk ratio: 3.6; [1.5, 8.3], p<0.001). Increased plasma arginase activity was highly correlated with increased intravascular hemolytic rate and, to a lesser extent, markers of inflammation and soluble adhesion molecule levels.
These data support a novel mechanism of disease in which hemolysis contributes to reduced NO bioavailability and endothelial dysfunction, via release of erythrocyte arginase, which limits arginine bioavailability, and release of erythrocyte hemoglobin, which scavenges NO. The arginine-to-ornithine and arginine-to-(ornithine plus citrulline) ratios are independently associated with pulmonary hypertension and increased mortality in patients with sickle cell disease.
PMCID: PMC2065861  PMID: 15998894
16.  Hemodynamic Characteristics and Predictors of Pulmonary Hypertension in Patients with Sickle Cell Disease 
The American Journal of Cardiology  2012;109(9):1353-1357.
Pulmonary hypertension (PH) is a common comorbidity of sickle cell disease (SCD) with an associated increased mortality risk, but its etiology is not well-understood. To evaluate the hemodynamic characteristics, clinical predictors, and cardiovascular manifestations of elevated pulmonary arterial pressure in this population, we performed noninvasive hemodynamic assessments of 135 patients with SCD using Doppler echocardiography. A diagnosis of PH was based on gender-, age-, and body mass index (BMI)-specific normal reference ranges for tricuspid regurgitation jet velocities (TRV). A high TRV was noted in 34 (25%) of patients. Pulmonary vascular resistance (PVR) was elevated in only 2 of the 34 patients (6%) with suspected PH, but was significantly higher than in those with a normal TRV. In univariate regression, TRV correlated with age, BMI, left atrial pressure, and right ventricular stroke volume, and was negatively associated with hemoglobin and glomerular filtration rate. Left atrial pressure, right ventricular stroke volume, and hemoglobin remained independent predictors of TRV in a multivariate model. A higher TRV was also associated with larger right ventricular and right atrial chamber sizes and higher N-terminal pro-brain natriuretic peptide levels. Our results suggest that the mild elevation in TRV often observed in patients with SCD is rarely associated with a high PVR, and that multiple factors – including the compensatory high output state associated with anemia, pulmonary venous hypertension, and a pulmonary vasculopathy – may contribute to an elevated pulmonary arterial pressure in these patients.
PMCID: PMC3327788  PMID: 22341923
Pulmonary hypertension; sickle cell disease; echocardiography
17.  Laboratory and Echocardiography Markers in Sickle Cell Patients with Leg Ulcers 
American journal of hematology  2011;86(8):705-708.
Chronic leg ulcers are a debilitating complication of sickle cell disease, associated with increased morbidity and perhaps mortality that affect 8 to 50% of patients. We evaluated the characteristics of SCD patients with a history of leg ulceration, including hemolytic rate, estimated pulmonary artery systolic pressure, and other parameters in a cohort of 505 adults with SCD.
Ninety four subjects (18%) had either active ulcers at enrollment or history of leg ulceration. Patients affected were older and predominantly had homozygous SS, lower body mass index, and pulse oximetry, higher tricuspid regurgitation velocities, markers of hemolysis, serum uric acid and serum NT-proBNP, when compared to subjects without such history.
In this prospective cohort of adults with SCD, we confirm that leg ulcers are still frequent and are associated with elevated TRVand markers of hemolysis. We describe a novel association of leg ulcer with hyperuricemia and oxygen desaturation and suggest potential implications for uric acid as a marker of vascular dysfunction.
PMCID: PMC3245712  PMID: 21630312
Sickle Cell Disease; Leg Ulcer; Pulmonary Hypertension; Hemolysis; Uric Acid
18.  Prospective evaluation of haemoglobin oxygen saturation at rest and after exercise in paediatric sickle cell disease patients 
British journal of haematology  2009;147(3):352-359.
Low steady state haemoglobin oxygen saturation in patients with sickle cell anaemia has been associated with the degree of anaemia and haemolysis. How much pulmonary dysfunction contributes to low saturation is not clear. In a prospective study of children and adolescents with sickle cell disease aged 3–20 years at steady state and matched controls, 52% of 391 patients versus 24% of 63 controls had steady state oxygen saturation <99% (P < 0·0001), 9% of patients versus no controls had saturation <95% (P = 0·008) and 8% of patients versus no controls had exercise-induced reduction in saturation ≥3%. Decreasing haemoglobin concentration (P ≤ 0·001) and increasing haemolysis (P ≤ 0·003) but not pulmonary function tests were independent predictors of both lower steady-state saturation and exercise-induced reduction in saturation. Neither history of stroke nor history of acute chest syndrome was significantly associated with lower steady-state oxygen saturation or exercise-induced reduction in saturation. Tricuspid regurgitation velocity was higher in patients with lower steady state haemoglobin oxygen saturation (P = 0·003) and with greater decline in oxygen saturation during the six-minute walk (P = 0·022). In conclusion, lower haemoglobin oxygen saturation is independently associated with increasing degrees of anaemia and haemolysis but not pulmonary function abnormalities among children and adolescents with sickle cell disease.
PMCID: PMC2769929  PMID: 19694721
sickle cell disease; paediatric; oxygen saturation; six-minute walk; pulmonary hypertension
19.  Cardiopulmonary Complications of Sickle Cell Disease: Role of Nitric Oxide and Hemolytic Anemia 
Medical advances in the management of patients with sickle cell disease, thalassemia, and other hemolytic anemias have led to significant increases in life expectancy. Improved public health, neonatal screening, parental and patient education, advances in red cell transfusion medicine, iron chelation therapy, penicillin prophylaxis for children, pneumococcal immunization, and hydroxyurea therapy have all likely contributed to this effect on longevity.1,2 Importantly, as a generation of patients with sickle cell disease and thalassemia ages, new chronic complications of these hemoglobinopathies develop. In this context, pulmonary hypertension is emerging as one of the leading causes of morbidity and mortality in adult sickle cell and thalassemia patients, and likely in patients with other hemolytic anemias. A common feature of both sickle cell disease and thalassemia is intravascular hemolysis and chronic anemia. Recent data suggest that chronic intravascular hemolysis is associated with a state of endothelial dysfunction characterized by reduced nitric oxide (NO) bioavailability, pro-oxidant and pro-inflammatory stress and coagulopathy, leading to vasomotor instability and ultimately producing a proliferative vasculopathy, a hallmark of which is the development of pulmonary hypertension in adulthood.3–5 In conclusion, pulmonary hypertension is common in patients with hereditary hemolytic anemias and is associated with a high risk of death in patients with sickle cell disease. New therapies targeting this vasculopathy and aimed at normalizing the vasodilator:vasoconstrictor balance are discussed.
PMCID: PMC2222547  PMID: 16304359
20.  Abnormalities in Cardiac Structure and Function in Adults with Sickle Cell Disease are not Associated with Pulmonary Hypertension 
In sickle cell disease (SCD), pulmonary hypertension (assessed by tricuspid regurgitant jet [TRJ] velocity ≥ 2.5 m/s) is associated with increased mortality. The relationships between TRJ velocity, left ventricular (LV) and right ventricular (RV) systolic and diastolic function (i.e., relaxation and compliance) have not been well characterized in SCD.
Design and Methods
Prospective study of 53 ambulatory SCD adults (age, mean: 34 years; range 21-65 years) and 33 African American controls to define the relationship between LV and RV function and TRJ velocity by use of echocardiography.
SCD subjects had larger left and right atrial volumes and increased LV mass compared to controls. When SCD cases were compared to controls, LV and RV relaxation (i.e., E’) were similar. Among SCD subjects, pulmonary hypertension (TRJ ≥ 2.5 m/s) was present in 40% of cases. Higher TRJ velocity was correlated with larger LA volumes and areas in SCD cases. Additionally, some measures of LV (peak A, lateral and septal annulus E/E’) and RV compliance (TV E/E’) were correlated with TRJ velocity. No other measures of LV/RV systolic function or LV diastolic function (i.e., relaxation and compliance) were associated with TRJ velocity.
Ambulatory adults with SCD exhibited structural (i.e., LV and RV chamber enlargement) and functional (i.e., higher surrogate measures of LV and RV filling pressure) abnormalities compared to the control group. In SCD subjects, few abnormalities of LV and RV structure/function were associated with TRJ velocity.
PMCID: PMC3200507  PMID: 21873028
Pulmonary hypertension; diastolic dysfunction; sickle cell disease
21.  Risk Factors for Death in 632 Patients with Sickle Cell Disease in the United States and United Kingdom 
PLoS ONE  2014;9(7):e99489.
The role of pulmonary hypertension as a cause of mortality in sickle cell disease (SCD) is controversial.
Methods and Results
We evaluated the relationship between an elevated estimated pulmonary artery systolic pressure and mortality in patients with SCD. We followed patients from the walk-PHaSST screening cohort for a median of 29 months. A tricuspid regurgitation velocity (TRV)≥3.0 m/s cuttof, which has a 67–75% positive predictive value for mean pulmonary artery pressure ≥25 mm Hg was used. Among 572 subjects, 11.2% had TRV≥3.0 m/sec. Among 582 with a measured NT-proBNP, 24.1% had values ≥160 pg/mL. Of 22 deaths during follow-up, 50% had a TRV≥3.0 m/sec. At 24 months the cumulative survival was 83% with TRV≥3.0 m/sec and 98% with TRV<3.0 m/sec (p<0.0001). The hazard ratios for death were 11.1 (95% CI 4.1–30.1; p<0.0001) for TRV≥3.0 m/sec, 4.6 (1.8–11.3; p = 0.001) for NT-proBNP≥160 pg/mL, and 14.9 (5.5–39.9; p<0.0001) for both TRV≥3.0 m/sec and NT-proBNP≥160 pg/mL. Age >47 years, male gender, chronic transfusions, WHO class III–IV, increased hemolytic markers, ferritin and creatinine were also associated with increased risk of death.
A TRV≥3.0 m/sec occurs in approximately 10% of individuals and has the highest risk for death of any measured variable.
The study is registered in with identifier
PMCID: PMC4079316  PMID: 24988120
22.  Venous thromboembolism in adults with sickle cell disease: A serious and under-recognized complication 
The American journal of medicine  2013;126(5):443-449.
Sickle cell disease is recognized as a hypercoagulable state; however the frequency and characteristics of venous thromboembolism in sickle cell patients have not been well-defined.
To establish the prevalence and risk factors for venous thromboembolism in a large cohort of patients with sickle cell disease and determine the relationship between venous thromboembolism and mortality.
We performed a cross-sectional study of 404 sickle cell disease patients cared for at the Sickle Cell Center for Adults at Johns Hopkins. Demographic, sickle cell disease-specific comorbidity, and venous thromboembolism data were collected on all patients.
101 patients (25%) had a history of venous thromboembolism with a median age at diagnosis of 29.9 years. A history of non-catheter-related venous thromboembolism was found in 18.8% of patients. Sickle variant genotypes conferred a higher risk of non-catheter-related venous thromboembolism compared to sickle cell anemia genotypes (SS/Sβ0) (relative risk (RR) 1.77, 95% confidence interval (CI) 1.18–2.66). Tricuspid regurgitant jet velocity ≥ 2.5 m/s was also associated with non-catheter-related venous thromboembolism (RR 1.65, CI 1.12–2.45). Thirty patients (7.4%) died during the study period. Adjusting for all variables, non-catheter-related venous thromboembolism was independently correlated with death (RR 3.63, CI 1.66–7.92).
Venous thromboembolism is common in adults with sickle cell disease. Sickle variant genotypes and tricuspid regurgitant jet velocity ≥ 2.5m/s are associated with non-catheter-related venous thromboembolism. In addition, non-catheter-related venous thromboembolism appears to be an independent risk factor for death in our cohort. These results suggest that disease-specific prophylaxis and treatment strategies for venous thromboembolism should be investigated in sickle cell disease patients.
PMCID: PMC3627211  PMID: 23582935
23.  Cardiovascular Abnormalities in Sickle Cell Disease 
Journal of the American College of Cardiology  2012;59(13):10.1016/j.jacc.2011.10.900.
Sickle cell disease is characterized by recurrent episodes of ischemia-reperfusion injury to multiple vital organ systems and a chronic hemolytic anemia, both contributing to progressive organ dysfunction. The introduction of treatments that induce protective fetal hemoglobin and reduce infectious complications has greatly prolonged survival. However, with increased longevity, cardiovascular complications are increasingly evident, with the notable development of a progressive proliferative systemic vasculopathy, pulmonary hypertension (PH) and left ventricular diastolic dysfunction. Pulmonary hypertension is reported in autopsy studies and numerous clinical studies have shown that increased pulmonary pressures are an important risk marker for mortality in these patients. In epidemiological studies, the development of PH is associated with intravascular hemolysis, cutaneous leg ulceration, renal insufficiency, iron overload and liver dysfunction. Chronic anemia in sickle cell disease results in cardiac chamber dilation and a compensatory increase in left ventricular mass. This is often accompanied by left ventricular diastolic dysfunction which has also been a strong independent predictor of mortality patients with sickle cell disease. Both PH and diastolic dysfunction are associated with marked abnormalities in exercise capacity in these patients. Sudden death is an increasingly recognized problem and further cardiac investigations are necessary to recognize and treat high-risk patients.
PMCID: PMC3881188  PMID: 22440212
Sickle; Cell; Disease
24.  Cardiopulmonary function in individuals with HIV infection in the antiretroviral therapy era 
AIDS (London, England)  2012;26(6):731-740.
To determine relationship of echocardiographic measures of pulmonary hypertension to lung function and inflammatory biomarkers in HIV-infected individuals.
Cross-sectional study of 116 HIV-infected outpatients.
Doppler-echocardiography and pulmonary function testing were performed. Induced sputum and plasma cytokines, sputum cell counts and differentials, markers of peripheral T cell activation, and serum N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured. Univariate and multivariate analyses determined relationship of echocardiographic variables to pulmonary function, inflammation, and NT-proBNP.
Mean estimated pulmonary artery systolic pressure (PASP) was 34.3 mmHg (SD 6.9) and mean tricuspid regurgitant jet velocity (TRV) was 2.5 m/sec (SD 0.32). Eighteen participants (15.5%) had PASP of at least 40 mmHg, and 9 (7.8%) had TRV of at least 3.0 m/sec. Elevated TRV was significantly associated with CD4 cell counts below 200 cells/μl and higher log HIV RNA levels. Forced expiratory volume in one second (FEV1) percent predicted, FEV1/forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLco) percent predicted were significantly lower in those with elevated PASP or TRV. Sputum interleukin-8, peripheral interleukin-8, peripheral interferon-γ levels, and CD8+ T-cell expression of CD69+ were associated increased with increasing PASP and TRV. Log NT-proBNP was significantly higher with increasing PASP and TRV. Left ventricular function was not associated with PASP or TRV.
Echocardiographic manifestations of pulmonary hypertension are common in HIV and are associated with respiratory symptoms, more advanced HIV disease, airway obstruction, abnormal DLco, and systemic and pulmonary inflammation. Pulmonary hypertension and COPD coexist in HIV and may arise secondary to common inflammatory mechanisms.
PMCID: PMC3606053  PMID: 22210636
HIV; pulmonary hypertension; emphysema; COPD; inflammation
25.  Clinical correlates of acute pulmonary events in children and adolescents with sickle cell disease* 
We aimed to identify risk factors for acute pulmonary events in children and adolescents in the Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH) study.
Patients with hemoglobin SS (n=376) and other sickle cell genotypes (n=127) aged 3-20 years were studied at four centers in a cross-sectional manner. A sub-group (n=293) was followed for a median of 21 months (range 9-35).
A patient-reported history of one or more acute pulmonary events, either acute chest syndrome (ACS) or pneumonia, was obtained in 195 hemoglobin SS patients (52%) and 51 patients with other genotypes (40%). By logistic regression, history of acute pulmonary events was independently associated with patient-reported history of asthma (p<0.0001), older age (p=0.001), >3 severe pain episodes in the preceding 12 months (p=0.002), higher tricuspid regurgitation velocity (TRV) (p=0.028), and higher white blood cell (WBC) count (p=0.043) among hemoglobin SS patients. History of acute pulmonary events was associated with >3 severe pain episodes (p=0.009) among patients with other genotypes. During follow-up, 43 patients (15%) had at least one new ACS episode including 11 without a baseline history of acute pulmonary events. History of acute pulmonary events (odds ratio 5.4; p<0.0001) and younger age (odds ratio 0.9; p=0.010) were independently associated with developing a new episode during follow-up.
Asthma history, frequent pain and higher values for TRV and WBC count were independently associated with history of acute pulmonary events in hemoglobin SS patients and frequent pain was associated in those with other genotypes. Measures to reduce pain episodes and control asthma may help to decrease the incidence of acute pulmonary events in SCD.
PMCID: PMC3689858  PMID: 23560516
sickle cell disease; acute chest syndrome; vaso-occlusive crisis; asthma; pain

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