Levosimendan for Perioperative Cardioprotection: Myth or Reality?

BACKGROUND: Levosimendan is a calcium sensitizer drug causing increased contractility in the myocardium and vasodilation in the vascular system. It is mainly used for the therapy of acute decompensated heart failure. Several studies on animals and humans provided evidence of the cardioprotective properties of levosimendan including preconditioning and anti-apoptotic. In view of these favorable effects, levosimendan has been tested in patients undergoing cardiac surgery for the prevention or treatment of low cardiac output syndrome. However, initial positive results from small studies have not been confirmed in three recent large trials. AIM: To summarize levosimendan mechanisms of action and clinical use and to review available evidence on its perioperative use in a cardiac surgery setting. METHODS: We searched two electronic medical databases for randomized controlled trials studying levosimendan in cardiac surgery patients, ranging from January 2000 to August 2017. Metaanalyses, consensus documents and retrospective studies were also reviewed. RESULTS: In the selected interval of time, 54 studies on the use of levosimendan in heart surgery have been performed. Early small size studies and meta-analyses have suggested that perioperative levosimendan infusion could diminish mortality and other adverse outcomes (i.e. intensive care unit stay and need for inotropic support). Instead, three recent large randomized controlled trials (LEVO-CTS, CHEETAH and LICORN) showed no significant survival benefits from levosimendan. However, in LEVO-CTS trial, prophylactic levosimendan administration significantly reduced the incidence of low cardiac output syndrome. CONCLUSIONS: Based on most recent randomized controlled trials, levosimendan, although effective for the treatment of acute heart failure, can't be recommended as standard therapy for the management of heart surgery patients. Further studies are needed to clarify whether selected subgroups of heart surgery patients may benefit from perioperative levosimendan infusion.

Left atrial myxoma development after radiofrequency ablation of an atrial flutter substrate.

A 51-year-old man developed symptoms (palpitations) related to a large left atrial mass attached to interatrial septum discovered by trans-thoracic heart ultrasonography. Six months earlier this patient had undergone radiofrequency ablation (RFA) of an atrial flutter substrate. The left atrial mass was removed surgically using cardiopulmonary bypass with disappearance of symptoms. A post-operative diagnosis of atrial myxoma was made. The present case shows that a big left-atrial tumor could manifest with only mild unspecific symptoms such as palpitations. It is not clear whether the development of myxomas could be related to RFA or occurrence of heart tumors after RFA (already reported in medical literature) or whether it could be just chance without a causal link with ablation procedures. .

Effects of vitamin C on fibroblasts from sporadic Alzheimer's disease patients.

Several therapies for Alzheimer's Disease (AD) are currently under investigation. Some studies have reported that concentration of vitamins in biological fluids are lower in AD patients compared to control subjects and clinical evidence has shown the therapeutic potential of vitamin C and E in delaying AD progression. However, the molecular mechanism(s) that are engaged upon their administration in the APP metabolism in vitro or in vivo still need clarifying. Here, we investigate the effects of vitamin C supplementation, at physiological concentration, in skin fibroblasts obtained from SAD and FAD patients. This study shows that SAD patients' fibroblasts exhibited the exclusive appearance of C-terminal fragments, derived from APP processing, without giving rise to the beta-amyloid peptide, other than corresponding decreased levels of lysosomal enzymes, such as beta-hexosaminidase, alpha-mannosidase and cathepsins B, L, and D.

Cathepsin D expression is decreased in Alzheimer's disease fibroblasts.

Cathepsin D (CTSD), a protease detectable in different cell types whose primary function is to degrade proteins by bulk proteolysis in lysosomes, has been suggested to be involved in Alzheimer's disease (AD). In fact, there is increasing evidence that disturbance of the normal balance and localization of cathepsins may contribute to neurodegeneration in AD [Nakanishi H. Neuronal and microglial cathepsins in aging and age-related diseases. Aging Res Rev 2003; 2(4):367-81]. Here, we provide evidence of an altered balance of CTSD in skin fibroblasts from patients affected either by sporadic or familial forms of AD. In particular, we demonstrate that CTSD is down regulated at both transcriptional and translational level and its processing is altered in AD fibroblasts. The oncogene Ras is involved in the regulation of CTSD, as high expression level of the constitutively active form of Ras in normal or AD fibroblasts induces CTSD down-regulation. p38 MAPK signalling pathway also appears to down-modulate CTSD level. Overall results reinforce the hypothesis that a lysosomal impairment may be involved in AD pathogenesis and can be detected not only in the CNS but also at a peripheral level.

Characterization of human Enah gene.

Enabled homolog (Enah) is a mammalian ortholog of Drosophila Enabled (Ena), which is genetically linked to the Drosophila Abl tyrosine phosphorylation signaling cascade and is required for normal neural development. Vertebrates have three Ena-related genes: Enah, VASP (vasodilator-stimulated phosphoprotein) and Ena/VASP like (EVL). These genes play an important role in linking signal transduction pathways to localized remodeling of the actin cytoskeleton. We isolated and sequenced a cDNA encoding human Enah. Comparison of the amino acid sequences of mouse (Mus musculus) and human (Homo sapiens) species shows 86.6% identity. The human protein appears longer than the mouse and additional amino acids are concentrated in a region containing repeats of the amino acid sequence LERER. The complete gene is about 157 kb and consists of 14 exons. Analysis of multiple tissue northern blot revealed a major transcript of about 4.8 kb in all tissue examined. Alternatively spliced isoforms were isolated by RT-PCR. The gene is differentially expressed and to gain insight factors affecting its expression we cloned and preliminarily characterized human Enah gene promoter.