Diagnosis of heart failure with preserved ejection fraction: a systematic narrative review of the evidence.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a common condition in clinical practice, affecting more than half of patients with HF. HFpEF is associated with morbidity and mortality and with considerable healthcare resource utilization and costs. Therefore, early diagnosis is crucial to facilitate prompt management, particularly initiation of sodium-glucose co-transporter 2 inhibitors. Although European guidelines define HFpEF as the presence of symptoms with or without signs of HF, left ventricular EF ≥ 50%, and objective evidence of cardiac structural and/or functional abnormalities, together with elevated natriuretic peptide levels, the diagnosis of HFpEF remains challenging. First, there is no clear consensus on how HFpEF should be defined. Furthermore, diagnostic tools, such as natriuretic peptide levels and resting echocardiogram findings, are significantly limited in the diagnosis of HFpEF. As a result, some patients are overdiagnosed (i.e., elderly people with comorbidities that mimic HF), although in other cases, HFpEF is overlooked. In this manuscript, we perform a systematic narrative review of the diagnostic approach to patients with HFpEF. We also propose a comprehensible algorithm that can be easily applied in daily clinical practice and could prove useful for confirming or ruling out a diagnosis of HFpEF.

Circulating Insulin-Like Growth Factor I is Involved in the Effect of High Fat Diet on Peripheral Amyloid ß Clearance.

Obesity is a risk factor for Alzheimer's disease (AD), but underlying mechanisms are not clear. We analyzed peripheral clearance of amyloid ß (Aß) in overweight mice because its systemic elimination may impact brain Aß load, a major landmark of AD pathology. We also analyzed whether circulating insulin-like growth factor I (IGF-I) intervenes in the effects of overweight as this growth factor modulates brain Aß clearance and is increased in the serum of overweight mice. Overweight mice showed increased Aß accumulation by the liver, the major site of elimination of systemic Aß, but unaltered brain Aß levels. We also found that Aß accumulation by hepatocytes is stimulated by IGF-I, and that mice with low serum IGF-I levels show reduced liver Aß accumulation-ameliorated by IGF-I administration, and unchanged brain Aß levels. In the brain, IGF-I favored the association of its receptor (IGF-IR) with the Aß precursor protein (APP), and at the same time, stimulated non-amyloidogenic processing of APP in astrocytes, as indicated by an increased sAPPα/sAPPß ratio after IGF-I treatment. Since serum IGF-I enters into the brain in an activity-dependent manner, we analyzed in overweight mice the effect of brain activation by environmental enrichment (EE) on brain IGF-IR phosphorylation and its association to APP, as a readout of IGF-I activity. After EE, significantly reduced brain IGF-IR phosphorylation and APP/IGF-IR association were found in overweight mice as compared to lean controls. Collectively, these results indicate that a high-fat diet influences peripheral clearance of Aß without affecting brain Aß load. Increased serum IGF-I likely contributes to enhanced peripheral Aß clearance in overweight mice, without affecting brain Aß load probably because its brain entrance is reduced.

The insulin-like growth factor I receptor regulates glucose transport by astrocytes.

Previous findings indicate that reducing brain insulin-like growth factor I receptor (IGF-IR) activity promotes ample neuroprotection. We now examined a possible action of IGF-IR on brain glucose transport to explain its wide protective activity, as energy availability is crucial for healthy tissue function. Using (18) FGlucose PET we found that shRNA interference of IGF-IR in mouse somatosensory cortex significantly increased glucose uptake upon sensory stimulation. In vivo microscopy using astrocyte specific staining showed that after IGF-IR shRNA injection in somatosensory cortex, astrocytes displayed greater increases in glucose uptake as compared to astrocytes in the scramble-injected side. Further, mice with the IGF-IR knock down in astrocytes showed increased glucose uptake in somatosensory cortex upon sensory stimulation. Analysis of underlying mechanisms indicated that IGF-IR interacts with glucose transporter 1 (GLUT1), the main facilitative glucose transporter in astrocytes, through a mechanism involving interactions with the scaffolding protein GIPC and the multicargo transporter LRP1 to retain GLUT1 inside the cell. These findings identify IGF-IR as a key modulator of brain glucose metabolism through its inhibitory action on astrocytic GLUT1 activity. GLIA 2016;64:1962-1971.

Insulin-like growth factor I sensitization rejuvenates sleep patterns in old mice.

Sleep disturbances are common during aging. Compared to young animals, old mice show altered sleep structure, with changes in both slow and fast electrocorticographic (ECoG) activity and fewer transitions between sleep and wake stages. Insulin-like growth factor I (IGF-I), which is involved in adaptive changes during aging, was previously shown to increase ECoG activity in young mice and monkeys. Furthermore, IGF-I shapes sleep architecture by modulating the activity of mouse orexin neurons in the lateral hypothalamus (LH). We now report that both ECoG activation and excitation of orexin neurons by systemic IGF-I are abrogated in old mice. Moreover, orthodromical responses of LH neurons are facilitated by either systemic or local IGF-I in young mice, but not in old ones. As orexin neurons of old mice show dysregulated IGF-I receptor (IGF-IR) expression, suggesting disturbed IGF-I sensitivity, we treated old mice with AIK3a305, a novel IGF-IR sensitizer, and observed restored responses to IGF-I and rejuvenation of sleep patterns. Thus, disturbed sleep structure in aging mice may be related to impaired IGF-I signaling onto orexin neurons, reflecting a broader loss of IGF-I activity in the aged mouse brain.

Insulin Regulates Astrocytic Glucose Handling Through Cooperation With IGF-I.

Brain activity requires a flux of glucose to active regions to sustain increased metabolic demands. Insulin, the main regulator of glucose handling in the body, has been traditionally considered not to intervene in this process. However, we now report that insulin modulates brain glucose metabolism by acting on astrocytes in concert with IGF-I. The cooperation of insulin and IGF-I is needed to recover neuronal activity after hypoglycemia. Analysis of underlying mechanisms show that the combined action of IGF-I and insulin synergistically stimulates a mitogen-activated protein kinase/protein kinase D pathway resulting in translocation of GLUT1 to the cell membrane through multiple protein-protein interactions involving the scaffolding protein GAIP-interacting protein C terminus and the GTPase RAC1. Our observations identify insulin-like peptides as physiological modulators of brain glucose handling, providing further support to consider the brain as a target organ in diabetes.

Prostaglandin signaling suppresses beneficial microglial function in Alzheimer's disease models.

Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation. In Alzheimer's disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/prostaglandin E2 (COX/PGE2) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. Here, we evaluated murine models that recapitulate microglial responses to Aß peptides and determined that microglia-specific deletion of the gene encoding the PGE2 receptor EP2 restores microglial chemotaxis and Aß clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits. Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE2/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD.