Impact of diabetes mellitus on myocardial lipid deposition: An autopsy study

Abstract

Lipid accumulation in the cardiac parenchyma has historically been known as fatty heart. Myocardial lipotoxicity and cardiac steatosis have been shown to be involved in the pathogenesis of obesity and diabetic mellitus (DM). Mutated adipose triglyceride lipase (ATGL), a key catalytic enzyme of triglyceride, has been found to cause human triglyceride deposit cardiomyovasculopathy (TGCV). Nevertheless, the significance of fatty heart in the disease process is still unclear. Here, we investigated myocardial lipid deposition (LD) in 73 autopsy cases. Nile blue staining revealed seven cases (9.5%) showing LD with elevated tissue triglyceride content, all of which suffered from DM. Immunohistochemically, ATGL expression was preserved in all tested cases. Rates of myocardial infarction and heart failure were higher in LD/DM cases than in non-LD cases. Semi-quantitative histological analysis revealed no significant differences in the degree of myocardial hypertrophy, myofibrillar loss, fibrosis, small vascular disease, inflammation or fat invasion between LD/DM and non-LD cases. However, more severe histological damage was seen in DM cases than in non-DM cases. Our data suggest that DM is a major risk for fatty heart with myocardial LD based on recent autopsy cases.

Introduction

Lipid degeneration of the heart, also known as fatty heart or cor adiposum, can be observed in certain pathological conditions such as infection, toxic diseases, hypoxia, metabolic disorders, hepatic diseases and anemia [2]. The 19th-century pathologist Rudolf Virchow was the first to distinguish between the two forms of fatty degeneration of the heart, namely adipogenesis surrounding the heart muscle and the accumulation of fatty droplets within the sarcolemma; Virchow also subsequently identified the condition known as essential fatty degeneration of the parenchyma [38]. Although the concept of fatty heart has been known for more than 300 years, the accumulation of neutral lipids in the tissues had been thought to be associated with nonspecific degeneration, retrogression, or inactivity without distinct pathophysiologic pathways [42]. From the 21st century, however, the significance of fatty heart has been re-discovered, starting with a report on lipotoxic cardiomyopathy in obese Zucker diabetic fatty rats [34], [46]. To date, myocardial lipotoxicity or cardiac steatosis has been demonstrated in several rodent models for obesity, diabetes mellitus (DM) or disrupted metabolic pathway [4], [27], [41], [45]. Specific intracellular pathways such as ceramide accumulation, induction of mitochondrial apoptotic pathways and increased oxidative stress have been shown to mediate cardiac dysfunction in these models [4], [27], [41], [45]. Myocardial steatosis has also been demonstrated in patients with obesity and type 2 DM using magnetic resonance imaging (MRI) [12], [30]. In an analysis of hearts obtained during the transplantation, nearly 30% of failing hearts displayed high levels of intra-myocardial lipid deposition, and significantly higher triglyceride (TG) deposition can be observed in patients with DM [32]. Among the general public, however, the incidence of fatty heart and its relationship with DM have not been fully elucidated.

The heart's high demand for energy is accommodated through mitochondrial oxidative phosphorylation, especially through β-oxidation of long-chain fatty acids. The myocardium serves as a site for labile storage of TG as a source of free fatty acids and intramyocardial TG degradation is accelerated by adrenergic stimulation followed by lipase activation [5], [24]. Hormone-sensitive lipase (HSL) was first purified from rat epididymal fat pads in the 1980s [11]. The second enzyme, adipose triglyceride lipase (ATGL), was discovered in 2004, ATGL functions in the degradation of lipid droplets, not only in adipocytes but also in non-adipotic cells [33], [44], [47]. ATGL-null mice suffer from a fatal cardiomyopathy involving massive TG accumulation in the cardiomyocytes [19]. Genetic mutation of the ATGL gene causes human myopathy (neutral lipid storage disease) [10], [24] and triglyceride-deposit cardiovasculopathy (TGCV) [19], [20]. The catalytic activity of ATGL is post-translationally regulated by protein kinase A or the other unknown kinase but full activation is required for binding with the activator protein, Comparative gene identification-58 (CGI-58) [40]. Genetic mutation of CGI-58 causes Chanarin–Dorfman syndrome, which is characterized by neutral lipid storage in various tissues and ichthyosis [23]. The most striking form of fatal cardiomyopathy, however, is seen in ATGL-null mice and in humans with TGCV [16], [19], [20]. Although ATGL deficiency is one distinct cause of fatty heart, the incidence of primary TGCV has not been clarified to date [19], [20].

In the present study, we retrospectively screened autopsy cases looking for fatty heart with myocardial lipid deposition (LD). Primary TGCV was also sought, and cases were subjected to with immunohistochemical analysis to determine ATGL expression. Clinico-pathological analysis and semi-quantitative histological analysis were performed to identify the characteristics of fatty heart cases.