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.

Clinical Utilisation of Wide-Field Optical Coherence Tomography and Angiography: A Narrative Review.

Many important abnormalities of the vitreous, retina and choroid are predominantly located in the peripheral retina. In some retinal diseases with both central and peripheral manifestations, pathological structural or vascular changes can be apparent in the periphery before they are detectable in the central retina. Conventional optical coherence tomography (OCT) and optical coherence tomography angiography (OCT-A) imaging only cover the most posterior 30° of the retina. Wide-field OCT (WF-OCT), though offering detailed cross-sectional imaging of the peripheral retina, is not yet systematically used in clinical practice. This narrative review provides a presentation of the utilisation of WF-OCT and WF-OCT-A in the diagnosis and monitoring of a variety of ophthalmological diseases and discusses the advantages and limitations of the technology. With the rapidly developing technology, multiple WF-OCT and WF-OCT-A devices are now commercially available and enable the clinician to obtain scans within a field of view up to 200°. As detailed in this review, several studies have shown promising results in the application of WF-OCT and WF-OCT-A in diseases of the retina, choroid and vitreous, such as retinal vein occlusion, diabetic retinopathy, ocular oncology, paediatric ophthalmology, uveitis and lesions of the vitreo-retinal interface. In conclusion, WF-OCT and WF-OCT-A can reliably produce high-quality, non-invasive images of the vitreous, retinal, and choroidal structures and vascularity covering the posterior pole as well as the mid and far periphery. These methods can be a valuable part of a multimodal imaging approach in the management of a variety of ocular conditions. Future studies are warranted to investigate the patient outcome benefits of implementation of WF-OCT and WF-OCT-A imaging in a real-life clinical setting.

Exudative Progression of Treatment-Naïve Nonexudative Macular Neovascularization in Age-Related Macular Degeneration: A Systematic Review With Meta-Analyses.

PURPOSE: To systematically review and report the rate of exudative progression over time in patients with nonexudative macular neovascularization (MNV) in age-related macular degeneration (AMD). DESIGN: Systematic review with prevalence meta-analyses and individual participant meta-analysis. METHODS: We searched 10 literature databases on March 26, 2023, for studies of consecutive patients with treatment-naïve nonexudative MNV in AMD. The primary outcome of interest was time from diagnosis to exudative progression. We conducted meta-analyses on the prevalence of exudative progression at 1 and 2 years. Where possible, we extracted individual participant data from studies and conducted an individual participant meta-analysis and explored the exudative progression using a time-to-event curve. RESULTS: We identified 16 eligible studies with a total of 384 eyes with nonexudative MNV. Exudative progression had occurred in 20.9% (95% CI 13.1%-29.8%) of eyes at 1 year and in 30.7% (95% CI 21.8%-40.4%) at 2 years. Similar results were observed in the individual participant meta-analysis, showing exudative progression in 18.9% (95% CI 13.5%-26.3%) of eyes at 1 year and 31.3% (95% CI 24.2%-40.0%) at 2 years. Risk factors for a fast exudative progression were the presence of subretinal lipid globules, large MNV areas, rapid MNV growth, growth in pigment epithelium detachment height and width, appearance of a branching pattern, and development of a hyporeflective halo around the MNV. CONCLUSIONS: Nonexudative MNVs in AMD are at high risk of exudative progression. Recognition of these lesions may allow for better individualized follow-up regimens in which closer monitoring may facilitate earlier diagnosis of exudative progression.

Prevalence of geographic atrophy in Nordic countries and number of patients potentially eligible for intravitreal complement inhibitor treatment: A systematic review with meta-analyses and forecasting study.

We systematically reviewed the literature on the prevalence of geographic atrophy (GA) in Nordic populations, conducted meta-analyses on age-stratified estimates, and calculated current and future number of patients and those potentially eligible for intravitreal complement inhibitor treatment. We followed the PRISMA guidelines, and our protocol was registered in PROSPERO. Ten databases were searched on 22 April 2023 for population-based studies of GA prevalence. Based on clinical descriptive analyses of GA and eligibility criteria of the phase III studies for intravitreal pegcetacoplan (complement C3 and C3b inhibitor), we were able to calculate the proportion of patients with GA potentially eligible for therapy. Finally, we extracted population data for Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) from Eurostat, applied prevalence statistics to the extracted census and forecasting data to estimate the number of patients with GA, and then applied the proportion eligible for intravitreal pegcetacoplan therapy. We identified six studies with a total of 10 159 individuals. Prevalence of GA was estimated to 0.4% (95% confidence intervals [CI]: 0.2%-0.8%), 1.5% (95% CI: 0.7%-2.6%), and 7.6% (95% CI: 4.6%-11.3%) for individuals aged 60-69, 70-79, and 80+ years, respectively. In Nordic countries, we estimate a total of 166 307 individuals with GA in 2023, increasing to 277 893 in 2050. Of these, 90 803 individuals in 2023, increasing to 151 730 in 2050, are potentially eligible for intravitreal complement inhibitor treatment. Considering these large numbers, our study highlights the importance of this topic in the coming years and its potential to significantly impact our clinical practice, organization, and staffing.

Metabolic Dysregulation in Adult Survivors of Pediatric Hematopoietic Stem Cell Transplantation: The Role of Incretins.

CONTEXT: Survivors of pediatric hematopoietic stem cell transplantation (HSCT) have increased risk of developing metabolic syndrome (MetS), but the mechanisms are poorly understood. OBJECTIVE: We aimed to test the hypothesis that insufficient secretion of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) plays a pathogenetic role in HSCT survivors with MetS. METHODS: This cross-sectional cohort study, conducted at the Danish national referral center for HSCT, studied 42 male HSCT survivors (median age 28.9 years) for a median 21.2 years from HSCT, along with 15 age- and sex-matched healthy controls. Main outcome measures were glucose metabolism and incretin hormones (by oral glucose tolerance test [OGTT]) and MetS criteria. The hypothesis was formulated before data collection. RESULTS: GLP-1, GIP, and glucagon during an OGTT were similar in patients and controls, with no overall difference between survivors with (24%) and without MetS. However, fasting glucagon was significantly higher in patients with hypertriglyceridemia (mean difference [MD]: 6.1 pmol/L; 95% CI, 1.5-10.8; P = 0.01), and correlated with HDL (MD: 4.7 mmol/L; 95% CI, -0.6 to 9.9; P = 0.08), android-gynoid ratio (correlation coefficient [r] = 0.6, P = 0.0001) and waist-hip ratio (r = 0.5, P = 0.002). A similar pattern was seen for GIP, correlating positively with triglyceride (MD: 60%; 95% CI, 44-82; P = 0.002). GIP levels were significantly increased in patients treated with total body irradiation (TBI) (MD: 165%; 95% CI, 118-230; P = 0.004), which was found to be a significant risk factor for MetS. CONCLUSION: This study demonstrates an altered production of incretin hormones in HSCT survivors previously treated with TBI, developing dyslipidemia and abdominal adiposity.

Cardiorespiratory fitness and physical performance after childhood hematopoietic stem cell transplantation: a systematic review and meta-analysis.

The effects of childhood hematopoietic stem cell transplantation (HSCT) on key organs can impair cardiorespiratory fitness, muscle strength, and physical performance. We aimed to provide an overview of childhood HSCT survivors' status on these parameters compared with healthy controls and discuss current insights into clinical risk factors. We performed a systematic search in six scientific databases, including studies published before April 2019 and performed a meta-analysis on cardiorespiratory fitness. Muscle strength and physical performance status were presented narratively. We included ten studies embodying 517 childhood HSCT survivors (mean 17.8 years at follow-up). The meta-analysis (n = 4 studies) showed that childhood HSCT survivors have lower cardiorespiratory fitness compared with healthy controls (Standard mean difference (SMD) -1.32 [95% CI -1-58 to -1.07]; I2 2%, p < 0.00001). Collectively, the studies indicated that childhood HSCT survivors have lower muscle strength (n = 4 studies) and physical performance (n = 3 studies) compared with healthy controls. Childhood HSCT survivors have impaired cardiorespiratory fitness years after ended treatment. Muscle strength and physical performance seem to be impaired, although these measures are insufficiently investigated. Associations between HSCT-specific clinical risk factors and cardiorespiratory fitness, muscle strength, and physical performance are required.

A Pilot Study Showing Acute Inhibitory Effect of GLP-1 on the Bone Resorption Marker CTX in Humans.

Bones have been suggested to be a target for glucagon-like peptide -1 (GLP-1); however, studies of the effects on human bones so far have given diverging results. We hypothesized that GLP-1, together with glucagon-like peptide-2 and glucose-dependent insulinotropic polypeptide, plays a role in the gut-bone axis. We examined the acute effect of three GLP-1 receptor ligands [GLP-1 (7-36)amide, GLP-1 (9-36)amide, and exenatide] on markers of bone remodeling. Eight healthy, normal-weight participants, with a mean age of 24.3 years, were studied for 4 days in a double-blinded, randomized clinical trial. Blood was collected before and after s.c. injection of GLP-1 (7-36)amide (1.5 nmol/kg), GLP-1 (9-36)amide (1.5 nmol/kg), exenatide (2.4 nmol/subject), or saline. Plasma was analyzed for bone markers and for osteoprotegerin (OPG), PTH, and IGF-1 levels. All ligands were tested in vitro for their cAMP-inducing activity on the human GLP-1 receptor. GLP-1 (7-36)amide decreased CTX-levels, compared with placebo (area under the curve [AUC] ±SD 0 to 120 min = -2143 ± 1294 % × min versus -883 ± 1557 % × min; p < 0.05). No difference was observed between placebo and GLP-1 (9-36)amide, or between placebo and exenatide, although exenatide had a similar potency as GLP-1 (7-36)amide for cAMP formation in vitro (EC50 of 0.093 and 0.054 nmol/L). However, exenatide reached maximum plasma concentration at 90 min versus 15 min for GLP-1 (7-36)amide, and plasma CTX was significantly decreased during the second hour of the study after exenatide injections compared with placebo (AUC ±SD -463.1 ± 218 % × min and -136 ± 91 % × min; p < 0.05). There was no effect of the injections on bone formation markers (P1NP and osteocalcin) or on OPG, PTH and IGF-1 levels. In conclusion, we show that GLP-1 receptor agonists, but not the primary metabolite GLP-1 (9-36)amide, decrease bone resorption, and suggest that GLP-1 may be part of the gut-bone axis. © 2019 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Road bike accidents involving cervical fractures presenting as cardiac arrest: a report of two cases.

We present two cases in which elderly male recreational cyclists suffered from cervical fractures and coinciding injuries of the spinal cord that subsequently led to cardiac arrest.Based on reports from eye witnesses and due to the low impact nature of the crashes, the two patients were initially considered as having cardiac arrest before falling of their bikes.The spinal cord injuries triggering cardiac arrest were acknowledged with delay, as the primary eliciting cause was considered cardiac disease in conjunction with all-out exercise. We suggest that increased focus should be made on possible cervical injuries even following low energy crashes in road cycling.

Estimates of insulin sensitivity and ß-cell function in children and adolescents with and without components of the metabolic syndrome.

INTRODUCTION: The accumulation of components of the metabolic syndrome (MetS) is associated with a disturbed glucose metabolism in obese children. AIM OF STUDY: The aim of the present study was to evaluate the association between MetS and estimates of insulin sensitivity and ß-cell function obtained from oral glucose tolerance test (OGTT)-derived indices in lean and obese children. MATERIAL AND METHODS: A 2-hour OGTT was administered in 83 children aged 7-17 years. 47 children were obese and recruited from a childhood obesity clinic and 36 were lean age- and sex-matched controls. Surrogate measures of insulin sensitivity and ß-cell function were assessed by the OGTT-derived indices: the Matsuda index, the insulinogenic index, and the oral disposition index. The severity of MetS was assessed by measures of waist circumference, blood pressure, and fasting levels of triglycerides, high-density lipoprotein cholesterol, and glucose. RESULTS: The 83 children were allocated to one of three groups according to the number of components of MetS: the median body mass index standard deviation score was 0.2 (range -0.6-2.9) in the low MetS risk group (n=36), 2.8 (0.1-4.1) in the high MetS risk group (n=25), and 2.9 (2.1-4.4) in the MetS group (n=22). An increasing number of MetS components were associated with a lower insulin sensitivity and an altered ß-cell function according to the Matsuda index (p<0.0001), the insulinogenic index (p<0.0001), and the oral disposition index (p=0.005). CONCLUSIONS: Children burdened by the accumulation of components of MetS exhibited a disturbed glucose metabolism as expressed by lowered peripheral insulin sensitivity and ß-cell function.

Searching for the physiological role of glucose-dependent insulinotropic polypeptide.

Glucose-dependent insulinotropic polypeptide (GIP) was established as a gut hormone more than 40 years ago, and there is good experimental support for its role as an incretin hormone although deletion of the GIP receptor or the GIP cells or GIP receptor mutations have only minor effects on glucose metabolism. Unlike the related hormone, GLP-1, GIP stimulates the secretion of glucagon, which in healthy individuals may help to stabilize glucose levels, but in people with type 2 diabetes may contribute to glucose intolerance. A role in lipid metabolism is supported by numerous indirect observations and by resistance to diet-induced obesity after deletion of the GIP receptor. However, a clear effect on lipid clearance could not be identified in humans, raising doubt about its importance. The GIP receptor is widely expressed in the body and also appears to be expressed on bone cells, and experimental studies in rodent point to effects on bone metabolism. Recent studies revealed pronounced inhibitory effects of GIP on bone resorption markers in humans and suggest that GIP may be (one of the) gastrointestinal regulators of bone turn-over. In support of this, a loss-of-function GIP receptor mutation in humans is associated with a marked increase in fracture risk. The lack of a reliable GIP receptor antagonist contributes to the uncertainty regarding the physiological role of GIP.

Glucose-dependent insulinotropic polypeptide inhibits bone resorption in humans.

BACKGROUND: In humans, the pronounced postprandial reduction in bone resorption (decreasing bone resorption markers by around 50%) has been suggested to be caused by gut hormones. Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone secreted postprandially from the small intestine. The hormone is known as an incretin hormone, but preclinical studies have suggested that it may also influence bone metabolism, showing both antiresorptive and anabolic effects as reflected by changes in biomechanical measures, microarchitecture, and activity of the bone cells in response to GIP stimulation. Its role in human bone homeostasis, however, is unknown. OBJECTIVE: To examine the effect of GIP administration on bone resorption in humans. MATERIALS AND METHODS: Plasma samples were obtained from 10 healthy subjects during four conditions: euglycemic (5 mmol/L) and hyperglycemic (12 mmol/L) 90-minute glucose clamps with co-infusion of GIP (4 pmol/kg/min for 15 min, followed by 2 pmol/kg/min for 45 min) or placebo. The samples were analyzed for concentrations of degradation products of C-terminal telopeptide of type I collagen (CTX), a bone resorption marker. RESULTS regarding effects on pancreatic hormone secretion have been published. RESULTS: During euglycemia, the decremental area under the curve in CTX was significantly (P < .001) higher during GIP infusion (2084 ± 686 % × min) compared to saline infusion (656 ± 295 % × min). During hyperglycemia, GIP infusion significantly (P < .001) augmented the decremental area under the curve to 2785 ± 446 % × minutes, compared to 1308 ± 448 % × minutes during saline infusion, with CTX values corresponding to 49% of basal values. CONCLUSIONS: We conclude that GIP reduces bone resorption in humans, interacting with a possible effect of hyperglycemia.