Pericoronary fat inflammation and Major Adverse Cardiac Events (MACE) in prediabetic patients with acute myocardial infarction: effects of metformin

Celestino Sardu, Nunzia D'Onofrio, Michele Torella, Michele Portoghese, Francesco Loreni, Simone Mureddu, Giuseppe Signoriello, Lucia Scisciola, Michelangela Barbieri, Maria Rosaria Rizzo, Marilena Galdiero, Marisa De Feo, Maria Luisa Balestrieri, Giuseppe Paolisso, Raffaele Marfella, Celestino Sardu, Nunzia D'Onofrio, Michele Torella, Michele Portoghese, Francesco Loreni, Simone Mureddu, Giuseppe Signoriello, Lucia Scisciola, Michelangela Barbieri, Maria Rosaria Rizzo, Marilena Galdiero, Marisa De Feo, Maria Luisa Balestrieri, Giuseppe Paolisso, Raffaele Marfella

Abstract

Background/objectives: Pericoronary adipose tissue inflammation might lead to the development and destabilization of coronary plaques in prediabetic patients. Here, we evaluated inflammation and leptin to adiponectin ratio in pericoronary fat from patients subjected to coronary artery bypass grafting (CABG) for acute myocardial infarction (AMI). Furthermore, we compared the 12-month prognosis of prediabetic patients compared to normoglycemic patients (NG). Finally, the effect of metformin therapy on pericoronary fat inflammation and 12-months prognosis in AMI-prediabetic patients was also evaluated.

Methods: An observational prospective study was conducted on patients with first AMI referred for CABG. Participants were divided in prediabetic and NG-patients. Prediabetic patients were divided in two groups; never-metformin-users and current-metformin-users receiving metformin therapy for almost 6 months before CABG. During the by-pass procedure on epicardial coronary portion, the pericoronary fat was removed from the surrounding stenosis area. The primary endpoints were the assessments of Major-Adverse-Cardiac-Events (MACE) at 12-month follow-up. Moreover, inflammatory tone was evaluated by measuring pericoronary fat levels of tumor necrosis factor-α (TNF-α), sirtuin 6 (SIRT6), and leptin to adiponectin ratio. Finally, inflammatory tone was correlated to the MACE during the 12-months follow-up.

Results: The MACE was 9.1% in all prediabetic patients and 3% in NG-patients. In prediabetic patients, current-metformin-users presented a significantly lower rate of MACE compared to prediabetic patients never-metformin-users. In addition, prediabetic patients showed higher inflammatory tone and leptin to adiponectin ratio in pericoronary fat compared to NG-patients (P < 0.001). Prediabetic never-metformin-users showed higher inflammatory tone and leptin to adiponectin ratio in pericoronary fat compared to current-metformin-users (P < 0.001). Remarkably, inflammatory tone and leptin to adiponectin ratio was significantly related to the MACE during the 12-months follow-up.

Conclusion: Prediabetes increase inflammatory burden in pericoronary adipose tissue. Metformin by reducing inflammatory tone and leptin to adiponectin ratio in pericoronary fat may improve prognosis in prediabetic patients with AMI. Trial registration Clinical Trial NCT03360981, Retrospectively Registered 7 January 2018.

Keywords: Acute myocardial infarction; Adipokines; Inflammation; Metformin; Pericoronary fat; Prediabetes.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow-chart of the study protocol
Fig. 2
Fig. 2
a Leptin to adiponectin ratio, in pericoronary fat specimens from 180 normal glucose patients and 180 prediabetic patients matched with propensity score analysis (PSM). (Boxplot, a plot type that displays the median, 25th, and 75th percentiles and range). *P < 0.01 vs. normal glucose patients. b Leptin to adiponectin ratio, in pericoronary fat specimens from 58 prediabetic never metformin users, and 58 prediabetic metformin users. ‡P < 0.01 vs. never metformin users. Data are mean ± SD
Fig. 3
Fig. 3
a Tumor necrosis factor-α (TNF-α) levels, in pericoronary fat specimens from 180 normal glucose patients and 180 prediabetic patients *P < 0.01 vs. normal glucose patients. b TNF-α levels, in pericoronary fat specimens from 58 prediabetic never metformin users and current metformin users. ‡P<0.01 vs. never metformin users. Data are mean ± SD
Fig. 4
Fig. 4
a Sirtuin-6 (SIRT6) levels, in pericoronary fat specimens from 180 normal glucose patients and 180 prediabetic patients matched with propensity score analysis (PSM). *P < 0.01 vs. normal glucose patients. b SIRT6 levels, in pericoronary fat specimens from 58 prediabetic never metformin users, and 58 prediabetic metformin users. ‡P < 0.01 vs never metformin users. Data are mean ± SD
Fig. 5
Fig. 5
a Regression analysis evidences a relationship between pericoronary fat leptin to adiponectin ratio and Tumor necrosis factor-α (TNF-α) levels in the overall study population. This analysis showed that the values of pericoronary TNF-α content (dependent variables) changed when pericoronary fat leptin to adiponectin ratio (independent variable) varied, while the other independent variables are held fixed. b Regression analysis evidences a relationship between pericoronary fat leptin to adiponectin ratio and sirtuin 6 (SIRT6) levels in the overall study population. This analysis showed that the values of pericoronary SIRT6 content (dependent variables) changed when fat pericoronary leptin to adiponectin ratio (independent variable) varied, while the other independent variables are held fixed
Fig. 6
Fig. 6
a Kaplan–Meier survival curves in PSM normal glucose and prediabetic patients. b Kaplan–Meier survival curves in PSM prediabetic never metformin users and prediabetic current metformin users. Overall survival and event-free survival are presented using, and compared using the log-rank test
Fig. 7
Fig. 7
Kaplan–Meier survival curves according to TNF-α (a), SIRT6 (b) and leptin (c) and adiponectin (d) terziles. SPSS version 23.0 (IBM statistics) was used for all statistical analyses. Overall survival and event-free survival are presented using, and compared using the log-rank test

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