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BackgroundThe independent prognostic impact of diabetes mellitus (DM) and prediabetes mellitus (pre‐DM) on survival outcomes in patients with chronic heart failure has been investigated in observational registries and randomized, clinical trials, but the results have been often inconclusive or conflicting. We examined the independent prognostic impact of DM and pre‐DM on survival outcomes in the GISSI‐HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca‐Heart Failure) trial.Methods and ResultsWe assessed the risk of all‐cause death and the composite of all‐cause death or cardiovascular hospitalization over a median follow‐up period of 3.9 years among the 6935 chronic heart failure participants of the GISSI‐HF trial, who were stratified by presence of DM (n=2852), pre‐DM (n=2013), and non‐DM (n=2070) at baseline. Compared with non‐DM patients, those with DM had remarkably higher incidence rates of all‐cause death (34.5% versus 24.6%) and the composite end point (63.6% versus 54.7%). Conversely, both event rates were similar between non‐DM patients and those with pre‐DM. Cox regression analysis showed that DM, but not pre‐DM, was associated with an increased risk of all‐cause death (adjusted hazard ratio, 1.43; 95% CI, 1.28–1.60) and of the composite end point (adjusted hazard ratio, 1.23; 95% CI, 1.13–1.32), independently of established risk factors. In the DM subgroup, higher hemoglobin A1c was also independently associated with increased risk of both study outcomes (all‐cause death: adjusted hazard ratio, 1.21; 95% CI, 1.02–1.43; and composite end point: adjusted hazard ratio, 1.14; 95% CI, 1.01–1.29, respectively).ConclusionsPresence of DM was independently associated with poor long‐term survival outcomes in patients with chronic heart failure.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00336336.

Cannabinoids exert complex actions on neurotransmitter systems involved in cognition, locomotion, appetite, but no information was available so far on the interactions between the endocannabinoid system and histaminergic neurons that command several, similar behavioural states and memory. In this study, we investigated the effect of cannabimimetic compounds on histamine release using the microdialysis technique in the brain of freely moving rats. We found that systemic administration of the cannabinoid receptors 1 (CB1-r) agonist arachidonyl-2'chloroethylamide/N-(2chloroethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (ACEA; 3 mg/kg) increased histamine release from the posterior hypothalamus, where the histaminergic tuberomamillary nuclei (TMN) are located. Local infusions of ACEA (150 nm) or R(+)-methanandamide (mAEA; 1 microm), another CB1-r agonist, in the TMN augmented histamine release from the TMN, as well as from two histaminergic projection areas, the nucleus basalis magnocellularis and the dorsal striatum. When the endocannabinoid uptake inhibitor AM404 was infused into the TMN, however, increased histamine release was observed only in the TMN. The cannabinoid-induced effects on histamine release were blocked by co-administrations with the CB1-r antagonist AM251. Using double-immunofluorescence labelling and confocal laser-scanning microscopy, CB1-r immunostaining was found in the hypothalamus, but was not localized onto histaminergic cells. The modulatory effect of cannabimimetic compounds on histamine release apparently did not involve inhibition of gamma-aminobutyric acid (GABA)ergic neurotransmission, which provides the main inhibitory input to the histaminergic neurons in the hypothalamus, as local infusions of ACEA did not modify GABA release from the TMN. These profound effects of cannabinoids on histaminergic neurotransmission may partially underlie some of the behavioural changes observed following exposure to cannabinoid-based drugs.

Consolidation of fear memory requires neural changes to occur in the basolateral amygdala (BLA), including modulation of histaminergic neurotransmission. We previously demonstrated that local blockade or activation of histamine H 3 receptors in the BLA impaired or ameliorated, respectively, retention of fear memory. The histamine H 3 receptor is a G-protein-coupled receptor (GPCR) displaying high constitutive activity that regulates histamine neurons in the brain. Proxyfan is a high-affinity histamine H 3 receptor protean agonist exhibiting the full spectrum of pharmacological activities, from full agonist to full inverse agonist depending on the competition between constitutively active and quiescent H 3 receptors in a given tissue or brain region. Therefore, protean agonists are powerful tools to investigate receptor conformation and may be useful in designing specific compounds selective for the various receptor conformations. In the present study we examined the effect of post-training, systemic or intra-BLA injections of proxyfan on contextual fear memory. Rats receiving intra-BLA, bilateral injections of 1.66 ng proxyfan immediately after fear conditioning showed stronger memory for the context-footshock association, as demonstrated by longer freezing assessed at retention performed 72 hr later compared to controls. Comparable results were obtained when doses as low as 0.04 mg/kg of proxyfan were injected systemically. Hence, our results suggest that proxyfan behaves as an H 3 receptor agonist with a low level of constitutive activity of the H 3 receptor in the rat BLA.

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