**9. Conclusions**

346 Lipid Metabolism

and CHF.

response to the stressing event inducing it but begins to be downregulated when PARP activation takes place, due to the increased oxidative stress [227], reducing NAD+ availability. The reduction in SIRT1, provided with an antiapoptotic function, and the compromised mitochondrial activity may contribute to the increased cellular death in chronically failing myocardium [228,229]. Overall we may conclude that some similarities exist between the metabolic and morphological alterations observed in 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

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

In the recent years the strict relationships between myocardial contractility and metabolism have been ascertained and a metabolic basis for cardiac contractile dysfunction verified in many clinical and experimental settings. Several metabolic alterations have been showed in CHF and septic myocardial dysfunction, their relationship with cardiac contractile dysfunction is not completely understood. They are probably a marker of the complex transcriptional and posttranscriptional alterations induced by the inflammatory, mechanical and metabolic stress the heart undergoes in both conditions and particularly of the coordinated compromise of mitochondrial function and of lipid oxidation but they represent also a direct inducer and amplifier of cellular damage. The significance of the morphological and metabolic alterations could be remarkably different in the slowly-evolving setting of CHF and in the acute one of the septic myocardial dysfunction, moreover the malignancy of the noxae underlying similar microscopic aspects may be very dissimilar. To understand in deep this aspect more thorough studies are needed. We currently do not know if they may represent a target for therapy because of the uncertain efficacy of the drugs until now used for this purpose but perhaps the light shed on the pathophysiological mechanism may give us an important help in the search for a future effective treatment.
