High-Sensitivity Cardiac Troponin T to Exclude Cardiac Involvement in TTR Variant Carriers and ATTRv Amyloidosis Patients.

(1) Background: Individuals carrying a pathogenic transthyretin gene variant (TTRv) are at high risk for developing hereditary transthyretin (ATTRv) amyloidosis and are routinely screened for the development of cardiomyopathy (ATTRv-CM). This study aims to evaluate whether the cardiac biomarkers N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) can be used to rule out ATTRv-CM. (2) Methods: In this retrospective case-control study, data from 46 ATTRv-CM patients and 101 TTRv carriers and ATTRv amyloidosis patients without cardiomyopathy were included. Binary logistic regression models were used to assess the ability of NT-proBNP and hs-cTnT to predict the diagnosis of ATTRv-CM. An optimal cutoff for the relevant biomarker(s) was determined based on a sensitivity of ≥99% and the highest possible percentage of additional tests avoided (%ATA) in the index dataset. (3) Results: Hs-cTnT demonstrated the highest predictive capabilities for ATTRv-CM. The addition of NT-proBNP did not improve the predictive model. A hs-cTnT cutoff of <6 ng/L resulted in a 97% sensitivity and a negative predictive value of 95% with a %ATA of 30% in the validation dataset. (4) Conclusion: In conclusion, hs-cTnT is a useful biomarker for excluding cardiac involvement in TTRv carriers and ATTRv amyloidosis patients and it has the potential to prevent unnecessary diagnostic procedures.

Erythroid progenitors from patients with low-risk myelodysplastic syndromes are dependent on the surrounding micro environment for their survival.

To investigate whether the type of programmed cell death of myelodysplastic erythroid cells depends on their cellular context, we performed studies on cells from patients with low-risk myelodysplastic syndromes. We compared erythroid cells (and their precursor cells) from the mononuclear cell fraction with those from the hematon fraction, which are compacted complexes of hematopoietic cells surrounded by their own micro-environment. In directly fixed materials, erythroblasts exhibited signs of autophagy with limited apoptosis (<3%) based on ultrastructural characteristics and immunogold labeling for activated caspase-3. After 24 h in culture, myelodysplastic erythroblasts exhibited a significant increase in apoptosis (22 ± 7% vs. 3 ± 2%, p = 0.001). In contrast, the myelodysplastic erythroblasts from the hematon fraction did not exhibit an increased tendency toward apoptosis after culture (7 ± 3.3% vs. 1.8 ± 2.3%), which was in line with results for normal bone marrow cells. The same dependency on the micro-environment was noted for immature erythroid progenitor cells. Myelodysplastic hematons exhibited distinct numbers of erythroid burst-forming units in association with an extensive network of stromal cells, whereas small numbers of erythroid burst-forming units were generated from the myelodysplastic mononuclear cells compared with normal mononuclear cells (10.2 ± 9 vs. 162 ± 125, p < 0.001). Co-culture of erythroid myelodysplastic cells in the presence of growth factors (vascular endothelial growth factor, leukemia inhibitory factor) or on the MS-5 stromal layer did not restore the expansion of erythroid precursor cells. These data indicate that surviving myelodysplastic erythroid progenitors become more vulnerable to programmed cell death when they are detached from their own micro-environment.

Increased glycocalicin index and normal thrombopoietin levels in patients with idiopathic thrombocytopenic purpura with a decreased rate of platelet production.

Platelet kinetic studies in idiopathic thrombocytopenic purpura (ITP) have shown that in a subgroup of patients a shortened mean platelet life (MPL) is associated with a decreased platelet production rate (PPR). Other methods of studying certain aspects of thrombocytopoiesis are the plasma concentrations of thrombopoietin and glycocalicin.

Increased peripheral platelet destruction and caspase-3-independent programmed cell death of bone marrow megakaryocytes in myelodysplastic patients.

To investigate underlying mechanisms of thrombocytopenia in myelodysplastic syndrome (MDS), radiolabeled platelet studies were performed in 30 MDS patients with platelet counts less than 100 x 10(9)/L. Furthermore, plasma thrombopoietin and glycocalicin index (a parameter of platelet or megakaryocyte destruction) were determined. Mean platelet life (MPL), corrected for the degree of thrombocytopenia, was reduced in 15 of 30 patients (4.3 +/- 0.9 days [mean +/- SD] vs 6.0 +/- 1.3, P = .0003). Platelet production rate (PPR) was reduced in 25 of 30 patients (68 +/- 34 x 10(9)/d vs 220 +/- 65, P < .0001). Thrombopoietin levels were not significantly correlated with the PPR. However, the glycocalicin index was significantly higher compared with controls (15 +/- 16 vs 0.7 +/- 0.2, P = .001) and significantly correlated with the PPR (P = .02, r = -0.5), but not with the MPL (P = 1.8). Ultrastructural studies demonstrated necrosis-like programmed cell death (PCD) in mature and immature megakaryocytes (n = 9). Immunohistochemistry of the bone marrow biopsies demonstrated no positive staining of MDS megakaryocytes for activated caspase-3 (n = 24) or cathepsin D (n = 21), while activated caspase-8 was demonstrated in a subgroup of patients (5/21) in less than 10% of megakaryocytes. These results indicate that the main cause of thrombocytopenia in MDS is caspase-3-independent necrosis-like PCD resulting in a decreased PPR in conjunction with an increased glycocalicin index.