Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart

Abstract

In animal models of lipotoxicity, accumulation of triglycerides within cardiomyocytes is associated with contractile dysfunction. However, whether intramyocardial lipid deposition is a feature of human heart failure remains to be established. We hypothesized that intramyocardial lipid accumulation is a common feature of non-ischemic heart failure and is associated with changes in gene expression similar to those found in an animal model of lipotoxicity. Intramyocardial lipid staining with oil red O and gene expression analysis was performed on heart tissue from 27 patients (9 female) with non-ischemic heart failure. We determined intramyocardial lipid, gene expression, and contractile function in hearts from 6 Zucker diabetic fatty (ZDF) and 6 Zucker lean (ZL) rats. Intramyocardial lipid overload was present in 30% of non-ischemic failing hearts. The highest levels of lipid staining were observed in patients with diabetes and obesity (BMI>30). Intramyocardial lipid deposition was associated with an up-regulation of peroxisome proliferator-activated receptor alpha (PPARalpha) -regulated genes, myosin heavy chain beta (MHC-beta), and tumor necrosis factor alpha (TNF-alpha). Intramyocardial lipid overload in the hearts of ZDF rats was associated with contractile dysfunction and changes in gene expression similar to changes found in failing human hearts with lipid overload. Our findings identify a subgroup of patients with heart failure and severe metabolic dysregulation characterized by intramyocardial triglyceride overload and changes in gene expression that are associated with contractile dysfunction.

Macrophages modulate cardiac function in lipotoxic cardiomyopathy

“…A key feature of the diabetic heart is the accumulation of myocardial lipid, which is thought to contribute to myocyte dysfunction and cell loss (15,20,23,25). However, the mechanisms involved in cardiac lipotoxicity in this disease are unresolved.…”

“…In many diabetic patients, this can occur in the absence of underlying coronary artery disease or hypertension, a phenomenon known as diabetic cardiomyopathy (1). The pathogenesis of diabetic cardiomyopathy is complex; however, myocardial lipid overload is a pathologic feature of this condition in humans and in animal models (6,7,12,25). The observation that cardiac myocyte lipid overload causes cardiomyopathy in genetic mouse models, without systemic abnormalities of insulin or glucose metabolism, supports the notion that excess lipids can be cardiotoxic (4,5,7,32).…”

Visceral Obesity as a Risk Marker of Multiorgan Damage

“…Изменение систолической и диастоли-ческой функции сердца, формирование неблагоприят-ного кардиального прогноза у пациентов с ожирением может быть опосредовано отложением липидов в кар-диомиоцитах [4]. По данным Sharma S., et al, при про-ведении у пациентов с ожирением, СД2 биопсии серд-ца, было отмечено 5-6-кратное увеличение содержа-ния липидов в кардиомиоцитах [40], ассоциирующееся с нарушением функционального состояния миокарда.…”

Lipid-induced cardiovascular diseases

“…And where lipotoxicity works as an elevating ectopic fat aggregation which cause worsen the condition local fat depots of CAD [30,31]. Indeed, the incidence of atherosclerosis is found to be elevated in patient showing insulin resistance with suffering from diabetes 2 mellitus [32], lipotoxicity is the major factor for insulin resistance [21].…”