Flow Cytometric Determination of Circulating Progenitor Cells in Patients With Pulmonary Arterial Hypertension: A Systematic Review

Figures

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  FIGURE 1. Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) flow diagram summarizing the process of literature identification, screening, and inclusion.

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  FIGURE 2. Subtypes of pulmonary arterial hypertension (PAH) represented in the studies of circulating progenitor cells meeting inclusion criteria for systematic review. A total of 647 PAH patients were reported in 19 studies. Congenital heart disease associated PAH (CHD‐PAH) was the second largest subgroup of patients (n = 184) and was further subdivided based on the designations from the original manuscripts. “Other” subtype, in green, included patients with schistosomiasis‐associated PAH (n = 1), disease‐associated PAH not otherwise specified (n = 20) and PAH not otherwise specified (n = 12).

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  FIGURE 3. Risk of bias assessment. Each category was scored as either low (green), intermediate (yellow) or high (red) risk of bias using a modified appraisal tool as described in the Methods. The flow cytometry score was used to determine whether flow data were measured in a valid and reliable way. A flow cytometry score of ≥ 5 is green, 4 is yellow; ≤ 3 is red. For the Toshner study, an average flow cytometry score was used (Giessen = 6, Cambridge = 4).

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  FIGURE 4. Frequency of common cell surface marker schemes used to define circulating progenitor cells by flow cytometry in PAH studies. Marker schemes reported in at least two studies are plotted on the y‐axis. The total number of counts is greater than the number of studies included in the systematic review (N = 19) because several studies reported results for more than one marker scheme. A complete list of the marker schemes reported in each study is summarized in Table 1.

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  FiGURE 5. Meta‐analysis of studies reporting numerical data for circulating progenitor cells in PAH patients compared to healthy controls. Standardized mean differences between PAH patients and healthy controls from each study were used for meta‐analysis. Studies were grouped based on shared marker schemes used for flow cytometry. Significant heterogeneity precluded a combined analysis of all 8 studies (I 2 = 90%, τ2 = 1.09, p < 0.01) as well as the 3 studies that investigated CD133+KDR+ cells (I 2 = 91%, τ2 = 1.46, p < 0.01). *Patients from these studies with a diagnosis other than PAH [sleep apnea (n = 3), sarcoidosis (n = 1), CTEPH (n = 15), pulmonary capillary hemangiomatosis (n = 1)] were not included in the meta‐analysis. ‡Data is from the Giessen cohort reported separately in the original manuscript.