**8. Cardiac lipotoxicity in chronic heart failure and sepsis**

In 1858 Virchow first reported intramyocyte lipid accumulation in patients with congestive heart failure, he referred to it as "lipid atrophy" of the myocardium [230]. At present the presence in the myocardial cell of neutral lipid droplets is ascribed to the altered glucose and lipid metabolism and to a mismatch between lipid delivery and oxidation. In normal conditions TG are stored only in adipocytes, under the control of PPAR with minimal presence of lipids in other tissues [231,232]; in this way adipocytes play indirectly a key role in the control of systemic glucose, lipid homeostasis and insulin sensitivity through the regulation of the serum level of FFA. In congenital lipodystrophy, a disease characterized by a decreased capacity of lipid storage in adipose tissue, the non-adipose organs accumulate TG and there is a premature cardiomyopathy [233]. When an overload of cellular FFA takes place caused by increased lipolysis or increased uptake (evident in clinical settings as in diabetes, in the experimental CD36 and LPL overexpression [234,235] or in settings of reduced FAO), lipid deposits in the myocardium and other organs may occur giving rise to the already seen phenomenon of lipotoxicity [236]. The contractile dysfunction caused by intramyocardial lipid accumulation is mediated at least partly by an altered expression of Sarco/Endoplasmic Reticulum Calcium ATPasi (SERCA2) as showed in specimen taken intraoperatively in patients with aortic stenosis and metabolic syndrome [237]. A diastolic dysfunction is also present, frequently preceding the systolic derangement and associated with interstitial fibrosis. Lipid accumulation is present in the heart of patients with CHF mainly in people with obesity, diabetes and metabolic syndrome. The relationship is bidirectional, insulin resistance predisposes to CHF and CHF increases insulin resistance. A reduced insulin sensitivity is observed in many patients with CHF, moreover its presence represents a risk factor for the eventual development of heart failure. Therefore the lipid accumulation alone without a reduced insulin sensitivity, obesity or metabolic syndrome can cause lipotoxicity. The importance of the cardiac isolated steatosis has been showed in the experimental context by demonstrating that myocardial overexpression of both PPAR and is associated with lipid accumulation and contractile dysfunction [238,239] probably because they stimulate more the uptake than the oxidation of FFA; moreover the PPAR activator fenofibrate can prevent the contractile dysfunction and the reduced calcium sensitivity in a rat model of LPS infusion further demonstrating the tight relationships between metabolic and contractile compromise [240]. Lipid deposits in the cardiomyocytes as TG in CHF is only a marker of an imbalance between the uptake and oxidation of FFA and not necessarily relates to toxic lipid byproducts formation. The chronic accumulation of neutral lipids is probably not, per se, immediately harmful for the myocardial cell in CHF but represents a mechanism of defence against the excess of the FFAs, more metabolically reactive, reaching it [241]. In the long term however lipid store may behaves as a time bomb because when a critical point is reached, either by accumulation of excessive quantity of lipid or by some event triggering an increased FAO, the accumulation of toxic byproducts such as ceramides, diacylglycerol, fatty acyl-CoAs and acyl-carnitine ensues damaging the myocardial cell.

The lipid accumulation in the heart during infections has been described since the '90 of the last century [242] however the only complete study in sepsis is the article by Rossi and colleagues [169]. They showed in septic myocardium an increased staining by the dye oil red O, specific for lipid, and attributed it to an altered metabolism of the myocardium.

These alterations are the morphological expression of the switch from lipid to glucose utilization in a setting in which lipolysis is increased and FAO reduced by PPAR downregulation and by acute mitochondrial dysfunction.

Very little is known about the significance of lipid accumulation in the septic myocardium; initially interpreted as a degenerative marker in infectious diseases it could have in the setting of the acute septic myocardiopathy a meaning considerably different from the chronic lipid accumulation in CHF even though the microscopic aspect is similar.

Certainly a lipidomic approach to the problem may be of great help.

In conclusion notwithstanding similar morphological aspects and the involvement of many common biochemical pathways the cardiac dysfunction in sepsis and in CHF may have different meanings and consequences.
