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Purpose: Chronic rejection induces the occurrence of orthotopic allograft transplantation (OAT) vasculopathy, which results in failure of the donor organ. Numerous studies have demonstrated that in addition to regulating blood sugar homeostasis, dipeptidyl peptidase-4 (DPP-4) inhibitors can also provide efficacious therapeutic and protective effects against cardiovascular diseases. However, their effects on OAT-induced vasculopathy remain unknown. Thus, the aim of this study was to investigate the direct effects of sitagliptin on OAT vasculopathy in vivo and in vitro., Methods: The PVG/Seac rat thoracic aorta graft to ACI/NKyo rat abdominal aorta model was used to explore the effects of sitagliptin on vasculopathy. Human endothelial progenitor cells (EPCs) were used to investigate the possible underlying mechanisms., Results: We demonstrated that sitagliptin decreases vasculopathy in OAT ACI/NKyo rats. Treatment with sitagliptin decreased BNP and HMGB1 levels, increased GLP-1 activity and stromal cell-derived factor 1α (SDF-1α) expression, elevated the number of circulating EPCs, and improved the differentiation possibility of mononuclear cells to EPCs ex vivo. However, in vitro studies showed that recombinant B-type natriuretic peptide (BNP) and high mobility group box 1 (HMGB1) impaired EPC function, whereas these phenomena were reversed by glucagon-like peptide 1 (GLP-1) receptor agonist treatment., Conclusions: We suggest that the mechanisms underlying sitagliptin-mediated inhibition of OAT vasculopathy probably occur through a direct increase in GLP-1 activity. In addition to the GLP-1-dependent pathway, sitagliptin may regulate SDF-1α levels and EPC function to reduce OAT-induced vascular injury. This study may provide new prevention and treatment strategies for DPP-4 inhibitors in chronic rejection-induced vasculopathy., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Anemia is prevalent in patients with heart failure and an independent prognostic sign of poor outcome. The current report is a meta-analysis of published clinical trials assessing the use of erythropoeisis stimulating agents (ESA) in heart failure (HF) patients with anemia., Methods: Literature and Medline search was performed to identify studies with control groups (case-control, cohort or randomized controlled trials) that examined the effect of ESA therapy in patients with HF and anemia., Results: Seven prospective controlled trials met inclusion criteria (n = 663 subjects). The ESA studied was darbepoetin in 4 trials and erythropoietin in 3 trials. Mean follow up period ranged from 12 to 27 weeks. Compared to placebo ESA therapy was associated with improvement in six cardiovascular parameters assessed by at least three of the analyzed trials, including increase in hemoglobin levels 2.35(95% confidence interval [Cl], 1.76-2.93, P < 0.00001), increase in exercise duration 0.91(95% Cl, 0.08-1.73, P = 0.03), improvement in New York Heart Association functional class -1.46(95% Cl, -2.32 to -0.60, P = 0.0009), improvement in 6-minute walk test 1.42(95% Cl, 0.31-2.54, P = 0.01), decrease in B-type natriuretic peptide -0.54(95% Cl, -1.03 to -0.06, P = 0.03), and improvement in peak oxygen consumption 0.93(95% Cl, 0.52-1.34, P < 0.00001)., Conclusion: In patients with heart failure and anemia, erythropoiesis stimulating agent therapy appears to have a positive effect on several important cardiovascular parameters, compared to control therapy. Large prospective randomized controlled trials are warranted to comprehensively evaluate the potential effects of erythropoiesis stimulating agents on clinical outcomes in heart failure patients with anemia.

Aim: Levosimendan improves central hemodynamics and symptoms in acutely decompensated chronic heart failure (CHF) patients. However, its effects on quality of life, emotional stress and functional capacity of patients with advanced CHF have not been properly investigated., Methods and Results: Sixty-three advanced CHF patients (NYHA III-IV, LVEF<30%) were randomized (2:1) to receive either a 24-h levosimendan infusion of 0.1 mug/kg/min or placebo. Questionnaires addressing quality of life [Kansas City Cardiomyopathy Questionnaire (KCCQ), functional and overall, Duke's Activity Status Index (DASI)] and emotional stress [Zung self-rating depression scale (SDS), Beck Depression Inventory (BDI)], as well as plasma BNP and 6-min walking distance (6MWT as a marker of exercise capacity) were assessed before treatment and at hospital discharge. A significant improvement in NYHA class (2.1 +/- 0.7 from 3.3 +/- 0.7, p < 0.01), 6 MWT (305 +/- 152 from 215 +/- 142 m, p < 0.01) and plasma BNP (598 +/- 398 from 1,078 +/- 756 pg/ml, p < 0.01) was observed post-treatment only in levosimendan-treated group. KCCQ functional (45 +/- 19 from 35 +/- 17%, p < 0.05) and overall (34 +/- 13 from 28 +/- 11%, p < 0.05), DASI (26 +/- 13 from 22 +/- 12, p < 0.05), Zung SDS (38 +/- 12 from 42 +/- 13, p < 0.01) and BDI (11 +/- 6 from 14 +/- 8, p < 0.05) scores also improved in levosimendan-treated patients, while remained unchanged in the placebo group. The hospital length stay was shorter in levosimendan group compared to placebo (3.2 +/- 1.7 versus 5.8 +/- 2.1 days, p < 0.01). Levosimendan-induced BNP reduction was significantly correlated with concomitant increase in 6MWT (r = 0.643, p < 0.001) as well as with the decrease of BDI (r = 0.30, p < 0.05) and Zung SDS (r = 0.25, p = 0.05)., Conclusion: Levosimendan seems to have a beneficial effect on quality of life, physical activity and emotional stress in advanced CHF patients, reducing concurrently hospitalization length.