GLP-1 increases heart rate by a direct action on the sinus node.

AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used to treat type 2 diabetes and obesity. Albeit cardiovascular outcomes generally improve, treatment with GLP-1 RAs is associated with increased heart rate, the mechanism of which is unclear. METHODS AND RESULTS: We employed a large animal model, the female landrace pig, and used multiple in-vivo and ex-vivo approaches including pharmacological challenges, electrophysiology and high-resolution mass spectrometry to explore how GLP-1 elicits an increase in heart rate. In anaesthetized pigs, neither cervical vagotomy, adrenergic blockers (alpha, beta or combined alpha-beta blockade), ganglionic blockade (hexamethonium) nor inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (ivabradine) abolished the marked chronotropic effect of GLP-1. GLP-1 administration to isolated perfused pig hearts also increased heart rate, which was abolished by GLP-1 receptor blockade. Electrophysiological characterization of GLP-1 effects in vivo and in isolated perfused hearts localized electrical modulation to the atria and conduction system. In isolated sinus nodes, GLP-1 administration shortened action potential cycle length of pacemaker cells and shifted the site of earliest activation. The effect was independent of HCN blockade. Collectively, these data support a direct effect of GLP-1 on GLP-1 receptors within the heart. Consistently, single nucleus RNA sequencing (snRNAseq) showed GLP-1 receptor expression in porcine pacemaker cells. Quantitative phosphoproteomics analyses of sinus node samples revealed that GLP-1 administration leads to phosphorylation changes of calcium cycling proteins of the sarcoplasmic reticulum, known to regulate heart rate. CONCLUSION: GLP-1 has direct chronotropic effects on the heart mediated by GLP-1 receptors in pacemaker cells of the sinus node, inducing changes in action potential morphology and the leading pacemaker site through a calcium signaling response characterized by PKA-dependent phosphorylation of Ca2+ cycling proteins involved in pace making. Targeting the pacemaker calcium clock may be a strategy to lower heart rate in GLP-1 RA recipients.

Eye-brain axis in microgravity and its implications for Spaceflight Associated Neuro-ocular Syndrome.

Long-duration human spaceflight can lead to changes in both the eye and the brain, which have been referred to as Spaceflight Associated Neuro-ocular Syndrome (SANS). These changes may manifest as a constellation of symptoms, which can include optic disc edema, optic nerve sheath distension, choroidal folds, globe flattening, hyperopic shift, and cotton wool spots. Although the underpinning mechanisms for SANS are not yet known, contributors may include intracranial interstitial fluid accumulation following microgravity induced headward fluid shift. Development and validation of SANS countermeasures contribute to our understanding of etiology and accelerate new technology including exercise modalities, Lower Body Negative Pressure suits, venous thigh cuffs, and Impedance Threshold Devices. However, significant knowledge gaps remain including biomarkers, a full set of countermeasures and/or treatment regimes, and finally reliable ground based analogs to accelerate the research. This review from the European Space Agency SANS expert group summarizes past research and current knowledge on SANS, potential countermeasures, and key knowledge gaps, to further our understanding, prevention, and treatment of SANS both during human spaceflight and future extraterrestrial surface exploration.

Intracranial pressure before and after cranioplasty: insights into intracranial physiology.

OBJECTIVE: Decompressive craniectomy (DC) is an emergency neurosurgical procedure used in cases of severe intracranial hypertension or impending intracranial herniation. The procedure is often lifesaving, but it exposes the brain to atmospheric pressure in the subsequent rehabilitation period, which changes intracranial physiology and probably leads to complications such as hydrocephalus, hygromas, and "syndrome of the trephined." The objective of the study was to study the effect of cranioplasty on intracranial pressure (ICP), postural ICP changes, and intracranial pulse wave amplitude (PWA). METHODS: The authors performed a prospective observational study including patients who underwent DC during a 12-month period. Telemetric ICP sensors were implanted in all patients at the time of DC. ICP was evaluated before and after cranioplasty during weekly measurement sessions including a standardized postural change program. RESULTS: Twelve of the 17 patients enrolled in the study had cranioplasty performed and were included in the present investigation. Their mean ICP in the supine position increased from -0.5 ± 4.8 mm Hg the week before cranioplasty to 6.3 ± 2.5 mm Hg the week after cranioplasty (p < 0.0001), whereas the mean ICP in the sitting position was unchanged (-1.2 ± 4.8 vs -1.1 ± 3.6 mm Hg, p = 0.90). The difference in ICP between the supine and sitting positions was minimal before cranioplasty (1.1 ± 1.8 mm Hg) and increased to 7.4 ± 3.6 mm Hg in the week following cranioplasty (p < 0.0001). During the succeeding 2 weeks of the follow-up period, the mean ICP in the supine and sitting positions decreased in parallel to, respectively, 4.6 ± 3.0 mm Hg (p = 0.0003) and -3.9 ± 2.7 mm Hg (p = 0.040), meaning that the postural ICP difference remained constant at around 8 mm Hg. The mean intracranial PWA increased from 0.7 ± 0.7 mm Hg to 2.9 ± 0.8 mm Hg after cranioplasty (p < 0.0001) and remained around 3 mm Hg throughout the following weeks. CONCLUSIONS: Cranioplasty restores normal intracranial physiology regarding postural ICP changes and intracranial PWA. These findings complement those of previous investigations on cerebral blood flow and cerebral metabolism in patients after decompressive craniectomy.