Influence of proliferation signal inhibitors on vascular endothelial growth factor production in heart transplant recipients - preliminary report.

Proliferation signal inhibitors (PSI) are especially beneficial for heart transplant recipients, but are rarely used due to frequent side effects. As they may be caused by vascular endothelial growth factor (VEGF), we performed a prospective cross-sectional pilot study to assess the influence of PSI and/or calcineurin inhibitors (CNI) presence in immunosuppressive protocols of heart transplant recipients on VEGF secretion. All electively screened heart transplant recipients willing to participate were enrolled in the study. The preliminary report was based on the results of the first 89 serum samples. The study group (n = 84) consisted of the PSI group (n = 14) further divided into the PSI + CNI subgroup (n = 10) and PSIw/oCNI subgroup (n = 4) based on concomitant CNI use, and the CNIw/oPSI group (n = 70) receiving CNI without PSI. The control group (n = 5) consisted of patients not requiring immunosuppression. VEGF was present in serum of 70 (83%) study group patients: median (range) 18 (0-316) pg/mL, mean 35 ± 57 pg/mL; in 13 (93%) PSI group patients: 22 (0-110) pg/mL, 28 ± 28 pg/mL, with 19 (8-20) pg/mL, 16 ± 6 pg/mL in the PSI + CNI subgroup, and 29 (0-110) pg/mL, 32 ± 32 pg/mL in the PSIw/oCNI subgroup. In the CNIw/oPSI group VEGF was present in 57 (81%) patients: 16 (0-316) pg/mL, 37 ± 62 pg/mL, and in the control group in 3 (60%) patients: 4 (0-110) pg/mL, 32 ± 48 pg/mL. None of the differences observed between any compared groups and/or subgroups was significant (χ(2) and Mann-Whitney U test). In conclusion, differences of VEGF concentration observed among groups imply the influence of PSI and CNI on VEGF production, but further studies involving higher numbers of participants are needed to prove it.

Advanced glycation end products and lipofuscin deposits share the same location in cardiocytes of the failing heart.

BACKGROUND: Disturbed glucose metabolism, particularly in diabetes type 2 (DM2), may result in advanced glycation end product (AGE) formation. One of the possible targets for this reaction is lipofuscin (LF), an intracytoplasmic garbage presumed to be a marker of physiologic and preterm aging of cells. The study was performed to seek for a relationship between AGE and LF in cardiocytes of the failing hearts. MATERIAL AND METHODS: Archived tissue samples from 136 hearts explanted before transplantation (in 14 pts. with ischemic cardiomyopathy (CM) and DM2; 8 pts. with dilated CM and DM2; 67 non-diabetic pts. with ischemic CM; 47 non-diabetic pts. with dilated CM), 14 autopsy cases with DM2, and 20 heart donors (control group) were involved in the study. Immunohistochemical localization of AGE was applied. The coexistence of lipofuscin and AGE was studied by LF autofluorescence in AGE-positive slides. RESULTS: LF granules inside AGE deposits were present in all studied groups with varying frequencies, but the differences were non-significant. LF granules joined significantly with dispersed patterns of AGE i.e. diffuse and mixed, whereas coincidence of LF and AGE forming granular pattern was rare. CONCLUSIONS: We demonstrate that LF may belong to the components of the AGE deposits. The frequency of this phenomenon is dependent on the AGE dispersion grade, but neither on diabetes nor cardiomyopathy presence.

Advanced glycation end product accumulation in the cardiomyocytes of heart failure patients with and without diabetes.

BACKGROUND: Non-enzymatic coupling of protein and lipid cellular structures with glucose leading to the formation of advanced glycation end products (AGE) plays a role in aging and the development of diabetic complications, but its contribution to myocardial pathology is unclear. We aimed to assess the role of heart failure on AGE formation in patients with or without diabetes mellitus type 2 (DM2). MATERIAL/METHODS: Heart tissue specimens from 136 patients undergoing transplantation were grouped as follows: 14 cases of ischemic cardiomyopathy (ICM) and DM2, 8 cases of dilated cardiomyopathy (DCM) and DM2, 67 cases of ICM without DM2, and 47 cases of DCM without DM2. Fourteen heart samples were from the autopsies of patients with DM2 without heart disease, and 20 heart samples were from organ donors in whom the heart was wasted. AGE deposits were localized immunohistochemically counted using a semiquantitative scale and characterized by their staining pattern. RESULTS: Positive staining was present in all samples from both cardiomyopathy groups with DM2, in 71% of healthy hearts from the DM2 subjects, in 51% of ICM non-diabetic hearts, and in 38% of DCM non-diabetic hearts, and in only 15% of the organ donors. Mixed-diffuse and granular AGE patterns were characteristic for DM2, while a diffuse pattern was more frequently observed in heart failure patients without diabetes. The semiquantitative results supported increased AGE accumulation in patients with DM2 and/or cardiomyopathy. CONCLUSIONS: The amount of AGE in cardiomyocytes increases significantly in both diabetes and heart failure, with a staining pattern typical for each condition.