The effect of empagliflozin on the development of chronic heart failure after myocardial infarction according to a 12-month prospective study

BACKGROUND: Although the positive cardiovascular effect of empagliflozin has been established, its influence on the formation of heart failure (HF) in patients with type 2 diabetes mellitus (T2D) after myocardial infarction (MI) remains unknown. AIM: To study the effect of empagliflozin on the formation of chronic HF after MI in patients having diabetes mellitus of type 2 (DM 2), according to 12-month follow-up data. MATERIALS AND METHODS: 47 patients with MI and DM 2 were included; 21 received standard therapy for MI and diabetes (group 1); 26 patients, in addition, received empagliflozin (group 2). The patients were investigated in 3 and 12 months, to assess the dynamics of glycemic control, 6-minute walk test, echocardiography. RESULTS: During postinfarction period, the 6-minute walk distance was increasing in group 1 in a lesser degree (p = 0.18) than in group 2 (49.5%, p = 0.0004). The ejection fraction got better particularly in group 2 (p = 0.002). At baseline, the proportions of patients having HF with reduced and mid-range ejection fraction were 85.7% and 82.4% in groups 1 and 2 (p = 0.56) but in 12 months decreased to 71.4% and 29.4% (p = 0.012). In empagliflozin group diastolic function was improved in a third of the patients (p = 0.041). The pulmonary artery systolic pressure was increasing in group 1 (by 10,4%, p = 0.041) but decreasing in group 2 (by 24,0%, p = 0.019). Glycemic control was better in group 2 than in group 1. CONCLUSION: According to 12-month follow-up data, empagliflozin has a positive effect on HF formation and symptoms in patients having MI and DM 2. This effect may be based on the ability of empagliflozin to improve the state of the heart including the delay of postinfarction remodeling, the improvement of pulmonary artery hemodynamics, systolic and diastolic function, the reduction of risk of chronic HF with reduced and mid-range ejection fraction

New insight into the mechanism of mitochondrial cytochrome c function.

We investigate functional role of the P76GTKMIFA83 fragment of the primary structure of cytochrome c. Based on the data obtained by the analysis of informational structure (ANIS), we propose a model of functioning of cytochrome c. According to this model, conformational rearrangements of the P76GTKMIFA83 loop fragment have a significant effect on conformational mobility of the heme. It is suggested that the conformational mobility of cytochrome c heme is responsible for its optimal orientation with respect to electron donor and acceptor within ubiquinol-cytochrome c oxidoreductase (complex III) and cytochrome c oxidase (complex IV), respectively, thus, ensuring electron transfer from complex III to complex IV. To validate the model, we design several mutant variants of horse cytochrome c with multiple substitutions of amino acid residues in the P76GTKMIFA83 sequence that reduce its ability to undergo conformational rearrangements. With this, we study the succinate-cytochrome c reductase and cytochrome c oxidase activities of rat liver mitoplasts in the presence of mutant variants of cytochrome c. The electron transport activity of the mutant variants decreases to different extent. Resonance Raman spectroscopy (RRS) and surface-enhanced Raman spectroscopy (SERS) data demonstrate, that all mutant cytochromes possess heme with the higher degree of ruffling deformation, than that of the wild-type (WT) cytochrome c. The increase in the ruffled deformation of the heme of oxidized cytochromes correlated with the decrease in the electron transport rate of ubiquinol-cytochrome c reductase (complex III). Besides, all mutant cytochromes have lower mobility of the pyrrol rings and methine bridges, than WT cytochrome c. We show that a decrease in electron transport activity in the mutant variants correlates with conformational changes and reduced mobility of heme porphyrin. This points to a significant role of the P76GTKMIFA83 fragment in the electron transport function of cytochrome c

Amino Acid Substitutions in the Non-Ordered Ω-Loop 70–85 Affect Electron Transfer Function and Secondary Structure of Mitochondrial Cytochrome c

The secondary structure of horse cytochrome c with mutations in the P76GTKMIFA83 site of the Ω-loop, exhibiting reduced efficiency of electron transfer, were studied. CD spectroscopy studies showed that the ordering of mutant structure increases by 3–6% compared to that of the WT molecules due to the higher content of β-structural elements. The IR spectroscopy data are consistent with the CD results and demonstrate that some α-helical elements change into β-structures, and the amount of the non-structured elements is decreased. The analysis of the 1H-NMR spectra demonstrated that cytochrome c mutants have a well-determined secondary structure with some specific features related to changes in the heme microenvironment. The observed changes in the structure of cytochrome c mutants are likely to be responsible for the decrease in the conformational mobility of the P76GTKMIFA83 sequence carrying mutations and for the decline in succinate:cytochrome c-reductase and cytochrome c-oxidase activities in the mitoplast system in the presence of these cytochromes c. We suggest that the decreased efficiency of the electron transfer of the studied cytochromes c may arise due to: (1) the change in the protein conformation in sites responsible for the interaction of cytochrome c with complexes III and IV and (2) the change in the heme conformation that deteriorates its optimal orientation towards donor and acceptor in complexes III and IV therefore slows down electron transfer. The results obtained are consistent with the previously proposed model of mitochondrial cytochrome c functioning associated with the deterministic mobility of protein globule parts

The informational structure of horse cytochrome <i>c</i> and its mutant forms: Result of the analyzis of the amino acid sequence using the ANIS method.

<p>(A) The hierarchically organized highest rank ELIS (continuous lines) and the fragments of the bipartite graph that cannot be revealed using the ANIS method (dashed line). X axis is the size of the smoothing interval a/2 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0178280#pone.0178280.ref021" target="_blank">21</a>], Y axis is the number N of amino acid in the primary structure of horse cytochrome <i>c</i>; (B), (C), (D) The hierarchically organized highest rank ELIS in mutant forms T78S/K79P, I81Y/A83Y/G84N, T78N/K79Y/M80I/I81M/F82N, respectively; (E) The spatial structure of horse cytochrome <i>c</i> (1HRC.PDB). The highest rank ELIS in the spatial structure of cytochrome c are shown. His18 and Met 80 residues coordinated to the Fe atom are indicated. The ADD- site (P76-A83) with the abnormally low density of first rank ELIS is shown by the arrows.</p