Cardiac synchronous and dys-synchronous remodeling in diabetes mellitus

Area of Science:

• Cardiovascular research
• Metabolic disorders
• Diabetology

Background:

• Hyperhomocysteinemia (HHcy) in diabetes results from impaired homocysteine (Hcy) metabolism and reduced renal clearance.
• Elevated Hcy induces oxidative stress, decreases peroxisome proliferators activated receptor (PPAR) expression, and exacerbates diabetic complications.
• The extracellular matrix (ECM) is crucial for endothelial-myocyte (E-M) coupling and cardiac synchrony.

Purpose of the Study:

• To investigate the mechanisms linking diabetes, HHcy, and cardiac dysfunction.
• To elucidate the role of ECM remodeling and E-M uncoupling in diabetic heart disease.
• To explore the relationship between PPAR signaling and cardiac tissue changes in this context.

Main Methods:

• Analysis of Hcy metabolism and renal clearance in diabetic models.
• Assessment of oxidative stress markers and PPAR expression in cardiac tissue.
• Evaluation of ECM composition, matrix metalloproteinase activity, and E-M interface integrity.
• Measurement of cardiac synchrony and diastolic function.

Main Results:

• Diabetes and HHcy lead to activated matrix metalloproteinase, causing ECM oxidation and fibrosis.
• This results in endothelial-myocyte (E-M) uncoupling, disrupting cardiac synchrony.
• Cardiac dyssynchronization and diastolic heart failure (DHF) are consequences of E-M uncoupling.
• Decreased thioredoxin, peroxiredoxin, and cardiac tissue inhibitor of metalloproteinase levels were observed, linked to PPARgamma antagonism.

Conclusions:

• Diabetes-associated hyperhomocysteinemia promotes cardiac fibrosis and endothelial-myocyte uncoupling.
• This uncoupling impairs cardiac synchrony, contributing to diastolic heart failure.
• PPARgamma antagonism plays a role in the observed molecular changes within the diabetic heart.