Cardiovasc Diabetol. 2022 Aug 05. 21(1):
146
Raffaele Marfella,
Nunzia D'Onofrio,
Gelsomina Mansueto,
Vincenzo Grimaldi,
Maria Consiglia Trotta,
Celestino Sardu,
Ferdinando Carlo Sasso,
Lucia Scisciola,
Cristiano Amarelli,
Salvatore Esposito,
Michele D'Amico,
Paolo Golino,
Marisa De Feo,
Giuseppe Signoriello,
Pasquale Paolisso,
Emanuele Gallinoro,
Marc Vanderheyden,
Ciro Maiello,
Maria Luisa Balestrieri,
Emanuele Barbato,
Claudio Napoli,
Giuseppe Paolisso.
BACKGROUND: High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control.OBJECTIVES: We investigated the possible effects of GlycACE2 on the anti-remodeling pathways of the RAS inhibitors by evaluating the levels of Angiotensin (Ang) 1-9, Ang 1-7, and Mas receptor (MasR), Nuclear-factor of activated T-cells (NFAT), and fibrosis in human hearts.
METHODS: We evaluated 197 first HTX recipients (107 non-T2DM, 90 T2DM). All patients were treated with angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) at hospital discharge. Patients underwent clinical evaluation (metabolic status, echocardiography, coronary CT-angiography, and endomyocardial biopsies). Biopsies were used to evaluate ACE2, GlycACE2, Ang 1-9, Ang 1-7, MasR, NAFT, and fibrosis.
RESULTS: GlycACE2 was higher in T2DM compared tonon-T2DM cardiomyocytes. Moreover, reduced expressions of Ang 1-9, Ang 1-7, and MasR were observed, suggesting impaired effects of RAS-inhibition in diabetic hearts. Accordingly, biopsies from T2DM recipients showed higher fibrosis than those from non-T2DM recipients. Notably, the expression of GlycACE2 in heart biopsies was strongly dependent on glycemic control, as reflected by the correlation between mean plasma HbA1c, evaluated quarterly during the 12-month follow-up, and GlycACE2 expression.
CONCLUSION: Poor glycemic control, favoring GlycACE2, may attenuate the cardioprotective effects of RAS-inhibition. However, the achievement of tight glycemic control normalizes the anti-remodeling effects of RAS-inhibition.
TRIAL REGISTRATION: https://clinicaltrials.gov/ NCT03546062.
Keywords: Diabetes; Diabetic cardiomyopathy; HbA1c; Heart transplantation; RAS-inhibition therapy