Relationship between metabolic and structural remodeling during DCM progression in human

Abstract

Introduction: Whether switch of energy substrates in dilated cardiomyopathy (DCM) is adaptive or causally related to myocardial pathology is still controversial. Thus the aim of our study was a link between structural and metabolic remodeling during DCM progression to heart failure (HF). Population study and methods. Archival RV tissue samples forty-four patients analysed histopathologically and ultrastructurally were subdivided into three groups according to EF determined at the time of admission: group (I) EF 45-55% (n=14, age 23,23±11,75 years), (II) EF 30-44% (n=15, age 24,67±10,36 years), (III) EF <30% (n=15, age 48,66±13,8 years). RNA from ten frozen samples belonging to mentioned groups was isolated and expression levels of PPARα, FAT/CD36, GLUT-4, and CPT-1 investigated. Results: Analysis revealed that with decrease of EF from 45-55% to about 35% was related to increased tissue fibrosis (from 6,15±5,45% to 8,29±5,26%) and cardiomyocytes hypertrophy (from diameter of 17,55±8,07 μm to 18,24±4,62 μm) with accompanying slight reduction of contractile apparatus and increase of mitochondria number and glycogen abundance, and transition of desmin expression from normal pattern to aggregates are characteristic features. Parallel, increase of PPARα and CPT-1, and GLUT-4 and decrease of FAT/CD36 gene expression was observed. While, in myocardial tissues of hearts with decreased EF to <30% was observed significant increase of fibrosis (14,23±12,4%), and not much progress in cardiomyocytes hypertrophy (cells diameter 18,75±4, 44 μm) but significant cell remodeling (related to significant loss of myofibrils, and glycogen, and mitochondria, and desmin cytoskeleton expression, and lipid droplets occurrence). These was accompanying by increased expression of genes - PPARα and FAT/CD36 and CPT-1 comparing to group II about 50% and 150% and 20% respectively, and lowered expression of GLUT4 gene. Conclusions: Obtained data reveled that switch of energy substrates precede cardiomyocytes structural disturbances in DCM. Furthermore, in early disease state glucose metabolism is activated probably to compensate decreased fatty acid transport, particularly that reserve of intracellular glucose is available. While, increase of PPARα and FAT/CD36 genes in later disease stage together with decrease of mitochondria number may lead to toxic lipids storage and cell injury. These data suggest the energetic metabolism as therapeutic purpose to prevent cardiac remodelling in DCM.