Nonalcoholic fatty liver disease (NAFLD) and cardiac lipotoxicity: Another piece of the puzzle

Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance and is considered the hepatic expression of the metabolic syndrome. Subjects with features of the metabolic syndrome are at risk of developing cardiovascular disease and coronary heart disease (CHD),1 and recent evidence suggest that this is the case in NAFLD as well. In a prospective study, the 14-year risk of mortality from cardiovascular causes was doubled in patients with biopsy-proven NAFLD compared with a reference population.2 In the Hoorn Study,3 raised alanine aminotransferase (ALT) at baseline increased the 10-year risk of CHD events, even after adjustment for the components of the metabolic syndrome. Coronary risk factors tend to cluster in patients with NAFLD, who exhibit more advanced atherosclerosis compared with controls.4 This observation is not surprising considering that the fatty liver is responsible for the overproduction of many cardiovascular disease risk factors, such as very low density lipoprotein, C-reactive protein, and clotting elements. Thus, conventional wisdom suggests that the hemodynamic or metabolic derangements associated with NAFLD may predispose to CHD and heart failure. ATP, adenosine triphosphate; CHD, coronary heart disease; FFA, free fatty acid; LV, left ventricle; MR, magnetic resonance; NAFLD, nonalcoholic fatty liver disease; PCr, phosphocreatine; T2DM, type 2 diabetes mellitus. Novel data indicate that type 2 diabetes (T2DM) and obesity per se may increase the risk for cardiac dysfunction and heart failure, independent of coronary disease and hypertension. In the early 19th century, Laennec first proposed the concept of fatty degeneration of the heart,5 a condition later defined as myocardial steatosis and associated with a greater risk for heart disease. Until recently, the study of myocardial steatosis in humans has been limited by difficulties in quantifying lipid content. Magnetic resonance (MR) imaging and MR spectroscopy techniques have recently allowed precise quantification of intracellular triglyceride in skeletal muscle, liver, and myocardium.6 In humans, myocardial triglyceride content increases progressively with body mass index; in cardiac biopsies, subjects with obesity or diabetes have intramyocardial lipid levels 5 to 6 times higher than controls.7 Myocardial steatosis causes alterations in myocardial substrate metabolism and efficiency (cardiac work/myocardial oxygen consumption) that occur early in the cascade of events leading to impaired left ventricle (LV) contractility.8 It is well established that the primary fuel for myocardium is represented by free fatty acid (FFA) in the fasting state and glucose in the fed state. However, an enhanced myocardial FFA utilization increases the oxygen cost of cardiac adenosine triphosphate (ATP) formation and reduces cardiac efficiency, rendering the heart more susceptible to energy depletion under conditions of reduced oxygen delivery or increased workload. Most of the evidence concerning the derangement of myocardial energetics in humans is based on studies with 31P-MR spectroscopy, which can be used to determine the ratio of phosphocreatine to ATP (PCr/ATP ratio), a powerful index of the energetic state of the heart.8 In obese women and in patients with T2DM, an increased uptake and oxidation of fatty acids is paralleled by a decrease in both glucose oxidation and cardiac mechanical efficiency.9 In patients with T2DM and CHD, liver fat content is a novel independent indicator of myocardial insulin resistance and reduced coronary functional capacity.10 However, direct evidence of the effect of hepatic steatosis on heart was lacking so far. The report by Perseghin and coworkers11 in this issue of HEPATOLOGY adds importantly to this body of information. Using cardiac magnetic resonance imaging and 31P-MR spectroscopy, the authors assessed intrapericardial and extrapericardial fat along with myocardial energy metabolism in young, well-matched nondiabetic men with or without fatty liver, measured by hepatic1H-MR spectroscopy. Individuals with fatty liver had an increased amount of fat in the epicardial area and displayed abnormal cardiac metabolism despite normal left ventricle morphological features and systolic/diastolic functions. The novel and relevant finding of this study is that in young men with fatty liver, cardiac metabolic remodeling appears to be an early event, independent of well-known risk factors for cardiovascular disease (age, obesity, hypertension, diabetes, exercise habits). Although the cross-sectional nature of this study does not allow conclusions regarding the future risks of cardiovascular events, it nevertheless does suggest that in patients with NAFLD abnormalities in cardiac metabolism may precede the development of functional and structural remodeling of the heart. In obese or diabetic patients, the metabolic switching of cardiac metabolism from glucose to fat has been attributed to the synergistic action of systemic and myocardial insulin resistance, increased fatty acid availability, and FFA-induced changes in transcription of genes involved in cardiac substrate selection, through activation of peroxisome proliferator-activated receptors.12 In NAFLD, the pathophysiological mechanisms of defective cardiac efficiency have not been characterized yet, but we might speculate that they involve insulin resistance, an abnormal lipid profile, and ultimately a low-grade inflammatory state (Fig. 1). Suggested pathophysiological mechanisms linking NAFLD and abnormal myocardial energy metabolism. See text for explanations. TG, triglycerides; FFA, free fatty acids; CRP, C-reactive protein. In individuals with CHD or T2DM, myocardial insulin resistance is inversely associated with LV ejection fraction.13 In a previous study,14 homeostatic model assessment (HOMA)2 was the most relevant predictive factor of the PCr/ATP ratio in obese men, but no association was found in the study of Perseghin et al.11 However, the HOMA2 is a rather crude index of insulin resistance, more suitable for larger populations, and the lack of correlation may be attributable to the limited number of subjects studied. On the other end, the PCr/ATP ratio was significantly associated with fasting plasma glucose and insulin. In the fasting state, the hepatic glucose production is the main determinant of blood glucose levels. Hepatic steatosis is associated with hepatic insulin resistance, that is, impaired suppression of hepatic glucose production, which in turn leads to hyperglycemia and compensatory hyperinsulinemia and may worsen systemic as well as cardiac insulin resistance. Thus, hepatic insulin resistance may be a possible link between NAFLD and defective cardiac energy metabolism. The liver plays a pivotal role in controlling the amount of lipids reaching the circulation. In patients with NAFLD, the increased FFAs availability may induce a detrimental effect on the PCr/ATP ratio through oxidative substrate competition or through an impairment of myocardial insulin signaling. Consistently, treatment with trimetazidine, a partial FFA oxidation inhibitor, induced improvement of the LV function and PCr/ATP ratio in patients with heart failure.15 Notably, in the study by Perseghin et al.,11 the extrapericardial and intrapericardial fat in NAFLD subjects appear to be increased and inversely correlated with the early/atrial peak filling rate, a parameter of diastolic function. This confirms previous studies in which epicardial fat was found to be negatively associated with the cardiac output.16 Heart and liver share the peculiarity of first-pass organs into which FFAs drain from a visceral fat depot, that is, epicardial and intraabdominal adipose tissue, respectively. Epicardial and intraabdominal fat show similar biochemical properties, including a higher lipolytic rate. In a previous study, liver steatosis was the strongest predictor of myocardial insulin sensitivity and perfusion in patients with T2DM.10 Thus, hepatic fat content may represent an indicator of a generalized condition of ectopic triglyceride deposition, involving the cardiac wall; in turn, lipids in the heart wall would be directly responsible for myocardial insulin resistance and energy impairment. Although the authors did not measure directly the myocardial fat content, cardiac lipotoxicity is a well-described phenomenon in insulin resistance, and is generally attributed to products of FFA excess metabolism.17 Interestingly, heart and liver share common mechanisms of lipotoxicity, although the resulting damage is different. In the heart, triglycerides are not toxic in a direct sense, but ceramide accumulation, formed via de novo synthesis from FFA, plays a central role in apoptosis of cardiomyocytes. Structural alterations in mitochondria can reduce cardiac function by providing an insufficient supply of ATP to cardiac myocytes or by increasing reactive oxygen species production, which has been associated with increased apoptosis, DNA damage, and decreased DNA repair.12 NAFLD is characterized by a low-grade inflammatory state in the liver and in the adipose tissue that may affect coronary vasculature as well as myocardial metabolism. In the study of Perseghin et al.,11 subjects with fatty liver had increased plasma levels of leptin and E-selectin, whereas adiponectin and resistin were reduced. Soluble forms of vascular adhesion molecules ICAM-1 and E-selectin are up-regulated in patients with higher liver fat content and may participate in endothelial dysfunction.18 Leptin is a potential mediator of cardiac hypertrophy in obesity, possibly by causing an increase in sympathetic vasoconstrictor tone and arterial blood pressure or through direct stimulation of protein synthesis in cardiomyocytes.19 Low adiponectin levels may impair the ability of the heart to adapt to acute and chronic stress, as suggested from studies of adiponectin deficiency in mice.20 In conclusion, there is a significant accumulation of triglyceride in the myocardium of young men with NAFLD, presumably resulting from fatty acid overflow to the heart in a generalized condition of ectopic fat excess. These features precede, and likely contribute to, LV overload and hypertrophy through mechanisms very similar to those observed in the progression of liver damage in NAFLD. Thus, the final effect of lipotoxicity varies according to the target organ: in the heart it translate into an impairment of energetic and mechanical efficiency, whereas in the liver a fibrogenic response is favored by the abundance of inflammatory cells. It will be important in future studies to determine whether therapies that will correct abnormal myocardial and hepatic substrate metabolism will translate to a lower prevalence of heart failure.