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.

Cardiovascular effects of oral appliance therapy in obstructive sleep apnea: A systematic review and meta-analysis.

Obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity and mortality. This study systematically reviews the effects of oral appliance therapy (OAT) on a broad spectrum of cardiovascular outcomes. A literature search was performed up to December 31st 2016. Twenty-five relevant full-text articles were retrieved. Sixteen articles were considered methodologically sufficient, including 11 randomized controlled trials. Pooled data of the RCTs showed significant reductions in daytime systolic and diastolic blood pressure compared to baseline, but no significant reductions in heart rate, except for daytime heart rate when compared to inactive/placebo OAT. OAT and continuous positive airway pressure (CPAP) were equally effective in reducing blood pressure. Studies assessing the effect of OAT on heart rate variability, circulating cardiovascular biomarkers, and endothelial function and arterial stiffness, generally involved small numbers of patients, and were heterogeneous and inconclusive. Studies assessing the effect of OAT on cardiac function showed no effects on echocardiographic outcomes. One observational study showed that OAT was as effective as CPAP in reducing cardiovascular death. It could be speculated that OAT may lead to a reduction in long-term cardiovascular morbidity and mortality in OSA patients. However, further methodologically high quality, longitudinal studies are warranted to address this key question.

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.

Platelet production rate predicts the response to prednisone therapy in patients with idiopathic thrombocytopenic purpura.

The predictive value of clinical and platelet kinetic parameters for treatment outcome in idiopathic thrombocytopenic purpura (ITP) was investigated in 75 patients with platelets355x10(9)/day) in 33%, 48%, and 19% of patients, respectively. All patients started with prednisone at diagnosis (1 mg/kg/day). Initial complete and partial response (CR/PR) rate was 84% and a durable CR/PR (>or=6 months without treatment) was attained in 44% of the patients. Durable CR/PR was noticed in 64% of the patients with decreased PPR during a median follow-up time without treatment of 81 (range 18-92) months, compared to 34% of the patients with normal or increased PPR during a median follow-up time without treatment of 141 (range 10-284) months (p=0.03). Splenectomy was performed in 32% of patients with decreased PPR and in 62% of patients with normal or increased PPR (p=0.03). In conclusion, ITP patients with suppressed PPR have a significant higher durable CR/PR rate to prednisone therapy and are less frequently exposed to splenectomy than those with a normal or increased PPR.

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.

Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura.

To investigate whether altered megakaryocyte morphology contributes to reduced platelet production in idiopathic thrombocytopenic purpura (ITP), ultrastructural analysis of megakaryocytes was performed in 11 ITP patients. Ultrastructural abnormalities compatible with (para-)apoptosis were present in 78% +/- 14% of ITP megakaryocytes, which could be reversed by in vivo treatment with prednisone and intravenous immunoglobulin. Immunohistochemistry of bone marrow biopsies of ITP patients with extensive apoptosis showed an increased number of megakaryocytes with activated caspase-3 compared with normal (28% +/- 4% versus 0%). No difference, however, was observed in the number of bone marrow megakaryocyte colony-forming units (ITP, 118 +/- 93/105 bone marrow cells; versus controls, 128 +/- 101/105 bone marrow cells; P =.7). To demonstrate that circulating antibodies might affect megakaryocytes, suspension cultures of CD34+ cells were performed with ITP or normal plasma. Morphology compatible with (para-)apoptosis could be induced in cultured megakaryocytes with ITP plasma (2 of 10 samples positive for antiplatelet autoantibodies). Finally, the plasma glycocalicin index, a parameter of platelet and megakaryocyte destruction, was increased in ITP (57 +/- 70 versus 0.7 +/- 0.2; P =.009) and correlated with the proportion of megakaryocytes showing (para-) apoptotic ultrastructure (P =.02; r = 0.7). In conclusion, most ITP megakaryocytes show ultrastructural features of (para-) apoptosis, probably due to action of factors present in ITP plasma.