Shoaib Alam

Hemodynamic Predictors of Mortality in Adults with Sickle Cell Disease

BACKGROUND Pulmonary hypertension (PH) in adults with sickle cell disease (SCD) is associated with early mortality, but no prior studies have evaluated quantitative relationships of mortality to physiological measures of pre- and postcapillary PH. OBJECTIVES To identify risk factors associated with mortality and to estimate the expected survival in a cohort of patients with SCD with PH documented by right heart catheterization. METHODS Nine-year follow-up data (median, 4.7 yr) from the National Institutes of Health SCD PH screening study are reported. A total of 529 adults with SCD were screened by echocardiography between 2001 and 2010 with no exclusion criteria. Hemodynamic data were collected from 84 patients. PH was defined as mean pulmonary artery pressure (PAP) ≥ 25 mm Hg. Survival rates were estimated by the Kaplan-Meier method, and mortality risk factors were analyzed by the Cox proportional hazards regression. MEASUREMENTS AND MAIN RESULTS Specific hemodynamic variables were independently related to mortality: mean PAP (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.05-2.45 per 10 mm Hg increase; P = 0.027), diastolic PAP (HR, 1.83; 95% CI, 1.09-3.08 per 10 mm Hg increase; P = 0.022), diastolic PAP - pulmonary capillary wedge pressure (HR, 2.19; 95% CI, 1.23-3.89 per 10 mm Hg increase; P = 0.008), transpulmonary gradient (HR, 1.78; 95% CI, 1.14-2.79 per 10 mm Hg increase; P = 0.011), and pulmonary vascular resistance (HR, 1.44; 95% CI, 1.09-1.89 per Wood unit increase; P = 0.009) as risk factors for mortality. CONCLUSIONS Mortality in adults with SCD and PH is proportional to the physiological severity of precapillary PH, demonstrating its prognostic and clinical relevance despite anemia-induced high cardiac output and less severely elevated pulmonary vascular resistance.

Elevated Transpulmonary Gradient and Cardiac Magnetic Resonance-Derived Right Ventricular Remodeling Predict Poor Outcomes in Sickle Cell Disease

Adults with sickle cell disease have a high prevalence of pulmonary hypertension. This picture is often complicated by concurrent left ventricular diastolic dysfunction and anemia-related changes in hemodynamics. The change in pressure across the pulmonary circulation reflected by the transpulmonary gradient is less clouded by anemia-related adaptations. We characterized the association of elevated transpulmonary gradient with right ventricular structure and function, exercise capacity and mortality. Data from 84 patients (age 41+/-13 years, 55% female [n=46], 82% hemoglobin SS [n=69]) with right heart catheterization from the Bethesda Sickle Cell Cohort were analyzed. Of the 84 patients, forty-one underwent cardiac magnetic resonance imaging within two days of right heart catheterization. Patients with a catheterization-derived transpulmonary gradient ≥12mmHg had more severe symptoms (p=0.013), shorter 6-minute walk distance (p=0.006), lower cardiac index (p<0.001), reduced right ventricular ejection fraction (p=0.002) and cardiac magnetic resonance imaging markers of adverse morphologic adaptation. An RVEF <32% derived from cardiac magnetic resonance predicted decreased survival (HR 3.70, 95% CI 1.04-13.12, p=0.030) and higher New York Heart Association classification (OR 9.29, p=0.018). In a multivariate model controlling for age and phenotype, transpulmonary gradient ≥12mmHg and right ventricular ejection fraction <32% were independently predictive of increased mortality (HR 5.47, 95% CI 1.13-26.42, p=0.035 and HR 5.11, 95% CI 1.13-23.13, p=0.034). Patients with sickle cell disease and elevated transpulmonary gradient have findings of maladaptive RV remodeling on cardiac magnetic resonance imaging. Elevated transpulmonary gradient and cardiac magnetic resonance-derived RV dysfunction independently predict higher mortality in sickle cell disease. Cardiac magnetic resonance may have a useful role in the clinical evaluation and non-invasive prognostication of adults with sickle cell disease and suspected pulmonary hypertension. This clinical trial was registered at clinicaltrials.gov identifier: [NCT00011648][1] NCT00081523, [NCT00023296][2], and [NCT00352430][3]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00011648&atom=%2Fhaematol%2Fearly%2F2015%2F11%2F13%2Fhaematol.2015.125229.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00023296&atom=%2Fhaematol%2Fearly%2F2015%2F11%2F13%2Fhaematol.2015.125229.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00352430&atom=%2Fhaematol%2Fearly%2F2015%2F11%2F13%2Fhaematol.2015.125229.atom

Characterizing non-linear dependencies among pairs of clinical variables and imaging data

Advances in computer-aided diagnosis (CAD) systems have shown the benefits of using computer-based techniques to obtain quantitative image measurements of the extent of a particular disease. Such measurements provide more accurate information that can be used to better study the associations between anatomical changes and clinical findings. Unfortunately, even with the use of quantitative image features, the correlations between anatomical changes and clinical findings are often not apparent and definite conclusions are difficult to reach. This paper uses nonparametric exploration techniques to demonstrate that even when the associations between two-variables seems weak, advanced properties of the associations can be studied and used to better understand the relationships between individual measurements. This paper uses quantitative imaging findings and clinical measurements of 85 patients with pulmonary fibrosis to demonstrate the advantages of non-linear dependency analysis. Results show that even when the correlation coefficients between imaging and clinical findings seem small, statistical measurements such as the maximum asymmetry score (MAS) and maximum edge value (MEV) can be used to better understand the hidden associations between the variables.

Prostacyclin-analog therapy in sickle cell pulmonary hypertension.

Sickle cell disease (SCD) is associated with pulmonary hypertension (PH) which results in high morbidity and mortality. There are well-established therapies for pulmonary arterial hypertension (PAH), but few reports about their use in SCDPH. We report the clinical course of 11 SCDPH patients on maximal supportive therapy including other pulmonary vasodilators, who received compassionate therapy with prostacyclin-analogs at four PH treatment centers. Inclusion criteria for this retrospective study included PH diagnosis by standard right heart catheterization (RHC), and prostacyclin-analog therapy via any route of delivery for at least four weeks. Data were collected subject to availability in the medical record, including type of prostacyclin-analog therapy, maximal dose and duration, and follow-up data at least 100 days after initiating therapy. Statistical analyses were performed using GraphPad Prism version 5.0 (La Jolla, CA, USA), using paired t-test and

Oscillatory haematopoiesis in adults with sickle cell disease treated with hydroxycarbamide.

Hydroxycarbamide therapy has been associated with significant oscillations in peripheral blood counts from myeloid, lymphoid and erythroid lineages in patients with polycythaemia vera and chronic myeloid leukaemia. We retrospectively evaluated serial blood counts over an 8‐year period from 44 adult patients with sickle cell disease receiving hydroxycarbamide. Platelet counts, leucocyte counts, haemoglobin values and reticulocyte counts, apportioned by hydroxycarbamide status, were analysed using a Lomb‐Scargle periodogram algorithm. Significant periodicities were present in one or more counts in 38 patients receiving hydroxycarbamide for a mean duration of 4·81 years. Platelet and leucocyte counts oscillated in 56·8% and 52·3% of patients, respectively. These oscillations generally became detectable within days of initiating therapy. During hydroxycarbamide therapy, the predominant periods of oscillation were 27 ± 1 d for platelet counts and 15 ± 1 d for leucocyte counts. Despite an absolute decrease in leucocyte and platelet counts during hydroxycarbamide treatment, the amplitudes between nadirs and zeniths remained similar regardless of exposure. Our observations appear consistent with previously proposed models of cyclic haematopoiesis, and document that hydroxycarbamide‐induced oscillations in blood counts are innocuous phenomena not limited to myeloproliferative disorders as described previously. We speculate the known cell cycle inhibitory properties of hydroxycarbamide may accentuate otherwise latent constitutive oscillatory haematopoiesis.

Non-invasive indicators of pulmonary hypertension from pulmonary veins quantification in sickle cell disease

Pulmonary hypertension is a common cause of death among patients with sickle cell disease. This retrospective study investigates the use of pulmonary vein analysis to diagnose pulmonary hypertension non-invasively with CT-Angiography images. Ten images from patients with pulmonary hypertension were matched with controls. An adaptive fast marching approach is applied in order to segment the left atrium and pulmonary veins, followed by a geodesic active contour to isolate the atrium. The ostia of the pulmonary veins are determined by computing the skeleton and finding the intersections with the contour of the atrium. 96.3% of the ostia are identified correctly by the technique. The diameters of the veins are then measured and their sum is computed at fixed distances from the ostium. These quantitative indicators are significantly larger in patients as compared to controls (p-values <; 0.01). Furthermore, the non-invasive estimations of the method present a high and significant correlation with the clinical hemodynamics measurements obtained from right heart catheterization.

RV dysfunction by MRI is associated with elevated transpulmonary gradient and poor prognosis in patients with sickle cell associated pulmonary hypertension

Background Patients with sickle cell disease (SCD) and pulmonary hypertension (PH) have increased mortality. SCD-PH is often complicated by high cardiac output (CO) related to anemia. The transpulmonary gradient (TPG) reflects a pressure differential across the pulmonary vascular bed without the confounding effect of CO (PVR=TPG/CO). Based on the cardiac transplant literature, a TPG ≥ 12 mmHg indicates significant pulmonary arterial hypertension (PAH). With PH, there is often morphologic adaptation by the right ventricle (RV). In idiopathic PAH, RV dilation and decreased function have been correlated with poor prognosis. We hypothesize that patients with SCD and a TPG ≥ 12 mmHg would have lower functional capacity, increased mortality, and evidence of RV dysfunction on cardiac MRI (CMR).

Computer-assisted diagnostic tool to quantify the pulmonary veins in sickle cell associated pulmonary hypertension

Pulmonary hypertension is a common cause of death among patients with sickle cell disease. This study investigates the use of pulmonary vein analysis to assist the diagnosis of pulmonary hypertension non-invasively with CT-Angiography images. The characterization of the pulmonary veins from CT presents two main challenges. Firstly, the number of pulmonary veins is unknown a priori and secondly, the contrast material is degraded when reaching the pulmonary veins, making the edges of these vessels to appear faint. Each image is first denoised and a fast marching approach is used to segment the left atrium and pulmonary veins. Afterward, a geodesic active contour is employed to isolate the left atrium. A thinning technique is then used to extract the skeleton of the atrium and the veins. The locations of the pulmonary veins ostia are determined by the intersection of the skeleton and the contour of the atrium. The diameters of the pulmonary veins are measured in each vein at fixed distances from the corresponding ostium, and for each distance, the sum of the diameters of all the veins is computed. These indicators are shown to be significantly larger in sickle-cell patients with pulmonary hypertension as compared to controls (p-values < 0.01).