Early indicators of neonatal-onset hereditary thrombotic thrombocytopenia purpura.

Background: Neonatal-onset hereditary thrombotic thrombocytopenia purpura (hTTP) is often misdiagnosed due to its rarity. It begins with jaundice, similar to infants with ABO incompatibility. Objective: To explore early indicators of neonatal-onset hTTP. Methods: This study was a retrospective case series of newborns with hTTP and ABO incompatibility. We compared the clinical characteristics and laboratory test results in these two groups. Results: This study included four hTTP patients and 20 ABO-incompatible newborns. All patients manifested disease during the neonatal period. There were equal numbers of males and females in each group. hTTP newborns showed earlier (median difference, 57.0 h; 95% confidence interval [CI], 24.0-65.0) and more severe hyperbilirubinemia (mean difference, 8.0 mg/dl; 95% CI, 3.8-12.1) than ABO-incompatible newborns. In hTTP newborns, anemia was more common within 7 days after birth than in ABO-incompatible newborns (odds ratio, 25.4; 95% CI, 1.2-551.6), and platelet counts were lower than in ABO-incompatible newborns (17 ± 12 × 109/L vs. 291 ± 76 × 109/L). The levels of serum creatinine (median difference, 51.8 µmol/L; 95% CI, 16.0-109.4) and blood urea nitrogen (median difference, 5.7 mmol/L; 95% CI, 2.8-38.7) were higher in hTTP newborns than in ABO-incompatible newborns. There were no significant differences in white blood cell counts, C-reactive protein, alanine aminotransferase, or albumin levels. Conclusions: Severe jaundice soon after birth, early anemia, and severe thrombocytopenia were more common in newborns with hTTP than ABO incompatibility. These are distinguishing early features of hTTP.

Adventitial Cell Atlas of wt (Wild Type) and ApoE (Apolipoprotein E)-Deficient Mice Defined by Single-Cell RNA Sequencing.

Objective- Vascular adventitia encompasses progenitors and is getting recognized as the major site of inflammation in early stage of atherosclerosis. However, the cellular atlas of the heterogeneous adventitial cells, the intercellular communication, the cellular response of adventitia to hyperlipidemia, and its contribution to atherosclerosis have been elusive. Approach and Results- Single-cell RNA sequencing was applied to wt (wild type) and ApoE (apolipoprotein E)-deficient aortic adventitia from 12-week-old C57BL/6J mice fed on normal laboratory diet with early stage of atherosclerosis. Unbiased clustering analysis revealed that the landscape of adventitial cells encompassed adventitial mesenchyme cells, immune cells (macrophages, T cells, and B cells), and some types of rare cells, for example, neuron, lymphatic endothelial cells, and innate lymphoid cells. Seurat clustering analysis singled out 6 nonimmune clusters with distinct transcriptomic profiles, in which there predominantly were stem/progenitor cell-like and proinflammatory population (Mesen II). In ApoE-deficient adventitia, resident macrophages were activated and related to increased myeloid cell infiltration in the adventitia. Cell communication analysis further elucidated enhanced interaction between a mesenchyme cluster and inflammatory macrophages in ApoE-deficient adventitia. In vitro transwell assay confirmed the proinflammatory role of SCA1+ (stem cell antigen 1 positive) Mesen II population with increased CCL2 (chemokine [C-C motif] ligand 2) secretion and thus increased capacity to attract immune cells in ApoE-deficient adventitia. Conclusions- Cell atlas defined by single-cell RNA sequencing depicted the heterogeneous cellular landscape of the adventitia and uncovered several types of cell populations. Furthermore, resident cell interaction with immune cells appears crucial at the early stage of atherosclerosis.

Acute Iloprost Inhalation Improves Right Ventricle Function in Pulmonary Artery Hypertension: A Cardiac Magnetic Resonance Study.

Background: Right ventricle (RV) function is among the most important prognostic factors for pulmonary arterial hypertension (PAH) patients. Inhaled iloprost, an inhaled member of the prostacyclin family, is effective for the treatment of severe PAH and acute RV failure. However, the acute effects of iloprost on RV physiology have not been thoroughly explored in the past. Materials and Methods: This prospective study involved 69 incident PAH patients, including 23 idiopathic PAH (IPAH) patients, 26 patients with PAH associated with connective tissue disease (CTD-PAH) and 20 with PAH associated with congenital heart disease (CHD-PAH). All patients underwent both right heart catheterization and cardiac magnetic resonance imaging at baseline and 20 min after 5 µg iloprost inhalation. Results: Acute iloprost inhalation reduced PVR from 13 ± 7 to 10 ± 6 Wood U (P < 0.001), increased RV ejection fraction (RVEF) from 31 ± 11 to 35 ± 12 % (P < 0.001), increased RV stroke volume from 53 ± 21 to 57 ± 22 ml (P < 0.001) and decreased RV end-diastolic volume from 179 ± 67 to 172 ± 69 ml (P < 0.001). Acute iloprost inhalation-induced RVEF improvement was correlated with the degree of PVR reduction (P < 0.001) in IPAH patients, but not in CTD-PAH or CHD-PAH patients. Conclusion: Acute iloprost inhalation improved RVEF, RV stroke volume and decreased RV volume in IPAH and CTD-PAH patients. Iloprost-induced RVEF increase was proportional to PVR reduction in IPAH patients, but not in CTD-PAH or CHD-PAH patients.

Direct bilirubin: A new risk factor of adverse outcome in idiopathic pulmonary arterial hypertension.

BACKGROUND: Previous studies have shown that elevated total bilirubin was associated with advanced heart failure, yet no study has ascertained the predictive value of direct serum bilirubin (DBIL) in idiopathic pulmonary arterial hypertension (IPAH). This study aimed to investigate the predictive value of both baseline and follow-up DBIL in patients with IPAH. METHODS: Serum DBIL was measured in 404 IPAH patients at enrollment. Almost 92% patients received specific drugs after diagnosis confirmed. Serum DBIL was repeated in 237 patients after a mean of 8.3months treatment. Survival rate among normal DBIL group and abnormal DBIL group was compared using the Kaplan-Meier method. The prognostic value of baseline variables was tested by Cox regression models. RESULTS: During median follow-up period of 40months, 153 patients died. Baseline DBIL levels were significantly higher in non-survivors compared with survivors (p<0.001). DBIL levels in survivors decreased significantly during PAH therapy, whereas there was almost no decrease in non-survivors. Patients with abnormal DBIL at baseline or during therapy had a significantly lower survival rates than those with normal DBIL group, according to Kaplan-Meier survival analysis (p=0.002 and p<0.0001, respectively). According to multivariate analyses, baseline DBIL was an independent risk factor of mortality in IPAH. CONCLUSIONS: Serum DBIL could predict severity and outcomes of IPAH: in particular, no obvious decrease in DBIL during PAH-specific drug therapy is strongly associated with worse prognosis in IPAH.

Elevated levels of plasma transforming growth factor-ß1 in idiopathic and heritable pulmonary arterial hypertension.

BACKGROUND: Aberrant transforming growth factor (TGF)-ß signaling is involved in the pathogenesis of pulmonary arterial hypertension (PAH). We aimed to investigate the predictive value of the upstream ligand of TGF-ß signaling (TGF-ß1) on long-term mortality and the clinical characteristics of patients with idiopathic pulmonary arterial hypertension (IPAH) and heritable PAH (HPAH). METHODS AND RESULTS: Plasma TGF-ß1 levels were measured in 151 IPAH and 65 HPAH patients retrospectively enrolled between January 2008 and March 2013, and compared to 61 healthy subjects. Data for mortality over time were obtained from hospital databases and from telephone follow-ups. The main outcome was all-cause death. Plasma TGF-ß1 was significantly higher in IPAH/HPAH patients compared to control subjects (4.74 vs. 2.61ng/mL, respectively; P<0.001). Mean follow-up time was 3.4±1.8years, during which 86 patients died. ROC curves were utilized to determine TGF-ß1 cutoff values. Compared to patients with TGF-ß1 of <3.74ng/mL, heart function was significantly impaired (percentage of patients with WHO functional class III/IV, 51.4% vs. 65.5%, P=0.043) and mortality risk was elevated (P=0.009) for patients with TGF-ß1>3.74ng/mL. However, the difference in mortality rate between patients with higher and lower TGF-ß1 levels was only statistically significant for female patients (P=0.004), despite a similar trend for male patients. Multivariate analyses revealed that TGF-ß1 (HR after log transformation base of 10: 2.623; 95%CI: 1.228-5.603; P=0.013) emerged as the independent predictor for all-cause mortality. CONCLUSION: High circulating levels of TGF-ß1 were an independent predictor of a poor outcome for IPAH/HPAH patients.