The Gly482Ser polymorphism in the peroxisome proliferator-activated receptor gamma coactivator-1α (PPARGC1A) has been reported to contribute to the development of left ventricular (LV) hypertrophy. Little is known, however, about its possible impact on cardiac dysfunction. Enhanced myocardial fibrosis accompanying increased LV mass might represent a link with coexisting functional abnormalities. We investigated the association between the PPARGC1A Gly482Ser polymorphism and LV morphology and performance in essential hypertension, with special consideration of fibrosis intensity. A total of 205 hypertensive patients (60±8 years) underwent echocardiography with assessment of cardiac morphology, LV systolic (strain and strain rate) and diastolic function (peak early diastolic mitral flow velocity/peak late diastolic mitral flow velocity (E/A) ratio, peak early diastolic myocardial velocity (Em), and E/e' ratio (where e' is the peak early diastolic mitral annular velocity)), evaluation of serum procollagen type III amino-terminal propeptide (PIIINP) and procollagen type I carboxy-terminal propeptide (PICP)-markers of fibrosis and the PPARGC1A Gly482Ser genotyping. Subjects with the Ser-Ser genotype demonstrated more profound LV hypertrophy and diastolic function impairment, and higher PICP/PIIINP than the Ser-Gly and Gly-Gly groups. In multivariable analysis, the presence of the Ser-Ser allele was an independent correlate of E/e' (β=0.17, P<0.02), Em (β=-0.18, P<0.01) and LV mass index (β=0.28, P<0.001). In conclusion, in hypertensive patients, the PPARGC1A Gly482Ser polymorphism is associated with LV hypertrophy and diastolic dysfunction, with the presence of the Ser-Ser allele promoting these abnormalities. One of the possible mechanisms mediating the adverse effect on diastolic performance might be a relative increase in the anabolism of rigid collagen type I over that of the more elastic collagen type III, as indicated by an increased ratio of PICP to PIIINP.

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Background. Platelet reactivity and response to antiplatelet drugs, acetylsalicylic acid (ASA) and clopidogrel, in patients with thrombocytopenia and thrombocythemia can have a potentially important effect on the outcome. The effectiveness and safety of antiplatelet drugs in such patients has not been well examined. Measuring the effect of ASA and clopidogrel on platelets could help guide the therapy. Nevertheless, platelet response to antiplatelet drugs is not routinely measured in platelet count disorders and relevant evidence is scarce. Aims. The study aimed to measure platelet reactivity and response to ASA and clopidogrel in patients with platelet count disorders. Materials and Methods. This was a cross-sectional study of consecutive patients hospitalized in cardiology and hematology departments in the years 2018–2019. The study included patients with thrombocytopenia (PLT < 150 G/L) and thrombocythemia (PLT > 450 G/L) on ASA or dual antiplatelet therapy (DAPT; ASA plus clopidogrel). Controls included patients on antiplatelet drugs with normal platelet count. Platelet reactivity was measured in whole blood (Multiplate aggregometer, Roche, Switzerland) using arachidonic acid (AA), adenosine-5′-diphosphate (ADP), and thrombin receptor agonist peptide-6 (TRAP) as agonists. Platelet aggregation was expressed in arbitrary units (AU). AA-induced aggregation was used as a measure of response to ASA with a cut-off above 30 AU showing high on-treatment platelet reactivity to ASA (HTPR-A). ADP-induced aggregation measured response to clopidogrel with a cut-off above 48 AU for high on-treatment platelet reactivity to clopidogrel (HTPR-C). TRAP-induced aggregation measured baseline platelet reactivity not affected by oral antiplatelet drugs. Results. The study included 174 patients. There were 64 patients with thrombocytopenia, 30 patients with chronic thrombocythemia, and 80 controls. All patients were on 75 mg of ASA and 32% of them additionally on 75 mg of clopidogrel due to a history of recent coronary artery angioplasty. AA- and ADP-induced aggregation was comparable between thrombocytopenic patients and controls (median (IQR) 19 (7–28) vs. 23 (15–38) for AA AU and 32 (16–44) vs. 50 (32–71) for ADP AU, respectively), while it was significantly higher in thrombocythemic patients (median (IQR) 80 (79–118) for AA AU and 124 (89–139) for ADP AU). TRAP-induced aggregation showed significantly lowest aggregation in thrombocytopenic (median (IQR) 41 (34–60) for TRAP AU) and highest in thrombocythemic patients (median (IQR) 137 (120–180) for TRAP AU). HTPR-A was frequent in thrombocythemic patients in comparison with thrombocytopenic patients and controls (60% vs. 4% vs. 15%, respectively; p < 0.0002 ). HTPR-C was highly common in thrombocythemic patients and least common in thrombocytopenic ones in comparison with controls (80% vs. 8% vs. 40%, respectively; p < 0.001 ). Conclusion. Chronic thrombocytopenia does not significantly affect platelet reactivity and response to ASA and clopidogrel in comparison with controls. Thrombocytosis significantly increases platelet reactivity and attenuates response to both ASA and clopidogrel.

Introduction There are limited data on platelet reactivity and response to antiplatelet drugs in patients with cardiogenic shock. Aim To assess platelet reactivity on dual antiplatelet therapy with acetylsalicylic acid (ASA) and ticagrelor, a novel potent P2Y12 receptor inhibitor, in patients with cardiogenic shock in the course of acute coronary syndrome (ACS) who received invasive treatment. Material and methods We enrolled 12 consecutive patients with ACS complicated by cardiogenic shock. To assess response to antiplatelet therapy during cardiogenic shock, only patients with symptoms persisting for at least 3 days and who completed a 5-day follow-up were included in the study. Patients received a loading dose of ASA (300 mg) and ticagrelor (180 mg), followed by a maintenance dose (ASA, 1 × 75 mg; ticagrelor, 2 × 90 mg). Blood samples for platelet function tests were collected. Platelet aggregation was assessed with a Multiplate whole-blood impedance aggregometer. Arachidonic acid (AA), adenosine diphosphate (ADP), and thrombin receptor-activating peptide (TRAP) were used as aggregation agonists. Results Response to antiplatelet therapy assessed by aggregometry showed numerically higher on-ASA platelet reactivity on day one and statistically significant higher on-ticagrelor platelet reactivity on day one in comparison with following days. There were 2 patients with high on ASA platelet reactivity and 3 with high on ticagrelor platelet reactivity, but only on the day one. Conclusions Some patients with cardiogenic shock in the course of ACS treated invasively show a lower response to ASA and ticagrelor only on the first day after invasive treatment, with a good response on subsequent days.

Background: Immune thrombocytopenia (ITP) is an autoimmune and inflammatory disease characterized by low platelet count with heterogeneous bleeding manifestations. Severe bleeding in ITP is not completely related with low platelet count. Thus, there is a great need for reliable indicators of the susceptibility of bleeding in ITP patients. Interleukin-37 (IL-37) is an anti-inflammatory cytokine that participates in the process of several inflammatory and autoimmune diseases. However, the role of IL-37 in the pathogenesis of ITP is unknown.Aims: Our study aimed to evaluate the regulatory role of IL-37 in the process of ITP and its association with disease severity. Methods: Plasma IL-37 was detected by enzyme-linked immunosorbent assay (ELISA). We cultured the monocytes/macrophages from ITP patients to investigate the regulatory role of IL-37 on monocytes/macrophages. Fcγ receptors (FcγRs) of macrophages were analyzed using flow cytometry and q-PCR. Signaling pathways were determined by western blotting. Phagocytic capacity of macrophages was measured by the engulfment of opsonized platelets.Results: Plasma and mRNA levels of the anti-inflammatory cytokine IL-37 were elevated in ITP patients with platelet counts below 30 × 10 9 /L compared to healthy controls and to ITP patients with platelet counts above 30 × 10 9 /L. Furthermore, plasma IL-37 levels correlated with the platelet number and IBLS bleeding scores of ITP patients. Specifically, ITP patients with skin and oral bleeding symptoms had higher plasma IL-37 levels than patients without these bleeding symptoms. Patients with more severe skin and oral bleeding exhibited higher plasma IL-37 levels, indicating that IL-37 could be a candidate in evaluating disease severity of ITP. IL-37 initiated an anti-inflammatory effect on monocytes/ macrophages from ITP patients by down-regulating the phosphorylation of MAPK, AKT, and NF-kB signaling pathways, which are pivotal in mediating inflammation. Moreover, IL-37 restored the balance of activating and inhibitory FcγRs (Figure 1) and decreased antibody-mediated platelet phagocytosis by monocytes/macrophages, suggesting that IL-37 might be a potential therapeutic agent in ITP. Summary/Conclusion: Our study demonstrated that ITP patients exhibited higher IL-37 expression, especially patients with severe hemorrhage or low platelet count. IL-37 decreased antibody-mediated platelet phagocytosis, restored the balance of activating and inhibitory FcγRs, and inhibited inflammatory activity via MAPK, AKT, and NF-kB signaling pathways among monocytes/macrophages. Therefore, IL-37 might be a candidate in evaluating the severity of ITP and a promising therapeutic agent for the management of ITP.