No abstract

Severe heart failure (HF) is characterized by profound alterations in cardiac metabolic phenotype, with down-regulation of the free fatty acid (FFA) oxidative pathway and marked increase in glucose oxidation. We tested whether fenofibrate, a pharmacological agonist of peroxisome proliferator-activated receptor-␣, the nuclear receptor that activates the expression of enzymes involved in FFA oxidation, can prevent metabolic alterations and modify the progression of HF. We administered 6.5 mg/kg/day p.o. fenofibrate to eight chronically instrumented dogs over the entire period of highfrequency left ventricular pacing (HF ϩ Feno). Eight additional HF dogs were not treated, and eight normal dogs were used as a control. Feno (14.1 Ϯ 1.6 mm Hg) compared with HF (18.7 Ϯ 1.3 mm Hg), but it increased up to 25 Ϯ 2 mm Hg, indicating end-stage failure, in both groups after 29 Ϯ 2 days of pacing. FFA oxidation was reduced by 40%, and glucose oxidation was increased by 150% in HF compared with control, changes that were prevented by fenofibrate. Consistently, the activity of myocardial medium chain acyl-CoA dehydrogenase, a marker enzyme of the FFA ␤-oxidation pathway, was reduced in HF versus control (1.46 Ϯ 0.25 versus 2.42 Ϯ 0.24 mol/min/gram wet weight (gww); p Ͻ 0.05) but not in HF ϩ Feno (1.85 Ϯ 0.18 mol/min/gww; N.S. versus control). Thus, preventing changes in myocardial substrate metabolism in the failing heart causes a modest improvement of cardiac function during the progression of the disease, with no effects on the onset of decompensation.The cardiac metabolic phenotype undergoes profound alterations during heart failure (HF), including defective energy production, lower mechanical efficiency, and a partial shift in energy substrate use . Oxidation of free fatty acids (FFA), which constitutes the preferential energy source for the normal heart, decreases in overt heart failure, whereas glucose oxidation markedly increases. The mechanisms underlying this phenomenon are numerous and complex. There is reduced myocardial expression and activity of key enzymes of the FFA oxidative pathway in different models of human as well as experimental heart failure (Sack et al., 1996;Martin et al., 2000;Rosenblatt et al., 2001;Osorio et al., 2002). The expression of these enzymes is under the control of the peroxisome proliferator-activated receptor (PPAR)-␣ and retinoid X receptor-␣ nuclear receptors that were also found down-regulated in the failing heart (Osorio et al., 2002;Karbowska et al., 2003). Whether such alterations in substrate metabolism play a role in the pathophysiological progression of heart failure remains an open question, with obvious implications for new therapeutic strategies based on metabolic modulators . It has

No abstract

No abstract

No abstract

Background-HDL molecules have an established role in the regression processes of atherosclerosis as well as a putative role as antiinflammatory agents. Our study investigated whether familial hypoalphalipoproteinemia, a genetic form of dyslipidemia characterized by very low HDL levels, might be associated with increased inflammation markers such as C-reactive protein. Key Words: lipoproteins Ⅲ C-reactive protein Ⅲ hypolipoproteinemia Ⅲ inflammation Ⅲ atherosclerosis T he hypothesis that elevated levels of plasma high-density lipoprotein (HDL) protect against coronary atherosclerotic disease (CAD) was initially proposed by Barr et al 1 in the 1950s and is now firmly established. 2 Conversely, equally well-established evidence shows that low plasma HDL levels lead to atherosclerosis and are also recognized to be a major independent risk factor for CAD. 2 Thus, HDL molecules can be considered the 2-faced Janus of the atherosclerotic process, which, in turn, is increasingly believed to be an inflammatory phenomenon. Atherosclerotic lesions show activation and proliferation of macrophages and T-lymphocytes, cytokine production, and oxidized lowdensity lipoprotein (LDL) accumulation. 3,4 We hypothesized that the link between low HDL levels and atherosclerosis may depend on an upregulation of inflammation mechanisms putatively induced by low HDL, which has been shown to act as a proinflammatory agent. 5,6 Therefore, we measured C-reactive protein (CRP) in a group of patients affected by familial hypoalphalipoproteinemia (Hypoalpha), an autosomal-dominant genetic trait. Hypoalpha subjects are characterized by extremely low plasma levels of HDL (Ͻ10th percentile), 7-9 together with reduced or normal LDL levels and normal or high triglyceride (TG) levels. Hypoalpha patients have greater susceptibility to early, severe coronary atherosclerosis. 10 -12 In the general population this trait has a prevalence of Ϸ0.5%, and it is 10 to 20 times more frequent in subjects with CAD who are Ͻ60 years of age.CRP is a well-established, sensitive marker of systemic inflammation and represents an independent risk factor for cardiovascular events in population studies as well as in angina patients. 13,14 Also, CRP seems to add predictive value to total cholesterol (TC) and HDL levels with regard to the risk of future myocardial infarction in subjects with hyperlipemia and elevated concentrations of CRP. 15 The hepatic synthesis of CRP is induced by cytokines such as interleukin-6 16 ; it accumulates in the arterial wall during the atheroscle- rotic process, stimulates production of the tissue factor by monocytes, 17 and induces the synthesis of adhesion molecules in endothelial cells. Hypoalpha subjects were compared with a group of healthy controls and divided according to the presence or absence of CAD, as documented by coronary angiography, to provide a model in which to photograph the inflammatory state before and after the occurrence of clinical vascular damage. Methods PatientsThe patients recruited for the study consisted of 50 c...

Tangier disease is one of the most severe forms of familial high-density lipoprotein (HDL) deficiency. Since its discovery it has been diagnosed in about 100 patients and is characterized by severe plasma deficiency or absence of HDL, apolipoprotein A-I (apoA-I, the major HDL apolipoprotein) and by accumulation of cholesteryl esters in many tissues throughout the body. The biochemical signs of this condition are plasma HDL concentrations less than 5 mg/dL, low total plasma cholesterol (below 150 mg/dL), and normal or high plasma triglycerides. Tangier disease is caused by mutations in the 'ATP-Binding Cassette transporter A1' (ABCA1) gene, which encodes the membrane transporter ABCA1. This transporter plays a key role in the first step of reverse cholesterol transport, through which the efflux of free cholesterol from peripheral cells is transferred to lipid-poor apoA-I. The Tangier disease clinical phenotype is inherited as an autosomal recessive trait, the biochemical phenotype is inherited as an autosomal co-dominant trait. Nearly all the children affected by Tangier disease were identified on the basis of large, yellow-orange tonsils, while half of the adult patients affected by Tangier disease came to medical attention because of symptoms of neuropathy. Diagnosis in the remaining subjects was related to the clinical features of hepatomegaly, splenomegaly, premature myocardial infarction (about 30% of Tangier disease cases) or stroke, thrombocytopenia, anemia, gastrointestinal disorders, corneal opacities, hypocholesterolemia, low HDL cholesterol, or following a familial screening of Tangier patients. To date there is no specific treatment for Tangier disease. Old and recently designed drugs, known to increase HDL levels, have been shown to be ineffective in Tangier patients. The possible and more realistic therapeutic strategy should be designed to obtain a selective increase of mature HDL concentration to restore cholesterol efflux. Recently designed drugs like the cholesteryl ester transfer protein (CETP) inhibitors dalcetrapib and anacetrapib and reconstituted forms of HDL could be considered until the development of gene therapy.

Sampietro T, Bigazzi F, Rossi G, Dal Pino B, Puntoni MR, Sbrana F, Chella E, Bionda A (CNR Institute of Clinical Physiology, Pisa; and University of Pisa, Pisa; Italy). Upregulation of the immune system in primary hypercholesterolaemia: effect of atorvastatin therapy. J Intern Med 2005; 257: 523-530.Objectives. High levels of plasma high sensitivity Creactive protein (CRP), sensitive to therapy with statins, have been described in hyperchole sterolaemia. In vitro evidence shows that CRP activates the complement system, which, in turn, leads to an increased expression of ICAM-1. Our objectives were to verify whether primary hypercholesterolaemia (PHC) is associated with an upregulation of the inflammatory/immune response, and whether this is sensitive to atorvastatin. Methods and results. We examined the levels of sICAM-1, C3, C4 complement fractions in 48 patients with PHC, with (CAD group) or without (No-CAD group) coronary artery disease (CAD) in comparison with a group of 48 healthy controls. The two patient groups were studied before and after atorvastatin therapy. Both hypercholesterolaemic groups showed higher mean values of sICAM-1, C3 and C4 (P < 0.0001) when compared with the controls. The two groups of patients responded differently to atorvastatin therapy. After 3 months, the C3 levels normalized in both groups of patients (P < 0.02 compared with basal values); C4 was greatly reduced only in the CAD group (P < 0.01). After 12 months of therapy, in CAD group C3 mean levels were still significantly lower than baseline values (P < 0.01); a further decrease in the C4 values (P < 0.05 with respect to levels after 3 months of therapy) and also a substantial reduction in sICAM-1 values (P < 0.001 with respect to basal values) were observed. Conclusions. High plasma values of C3 and C4 in PHC cluster with high values of sICAM-1, distinguish subjects with CAD and could be used to monitor the anti-inflammatory effect of statin therapy in these patients.